Optically active azabicyclo ring derivative

ABSTRACT

The compound of formula (1a) wherein p is 1 or 2, R 1 -R 4  are hydrogen atom or the like, and a-d are 1 or 2, or a pharmaceutically acceptable salt thereof, which has an antitumor effect by inhibiting the binding between a MLL fusion protein that is infused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.16/629,739, filed Jan. 9, 2020, which is a 35 U.S.C. § 371 nationalstage patent application of International Application No.PCT/JP2019/033234, filed Aug. 26, 2019, which is based on and claims thebenefits of priority to Japanese Application No. 2018-158315, filed onAug. 27, 2018. The entire contents of these applications areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an optically active azabicyclo ringderivative useful as a medicament, or a pharmaceutically acceptable saltthereof, and a pharmaceutical composition comprising it, or a medicamentcomprising the composition for treating or preventing conditions relatedto the binding between menin and MLL.

BACKGROUND ART

MLL leukemia is a disease that accounts for about 6 to 7% of acutemyeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and about1100 people are newly diagnosed with MLL leukemia each year in America.It has been reported that major fusion partner genes that cause MLLleukemia are likely to be AF9, ELL, ENL, AF10, and AF6 in AML, and AF4,ENL, and AF9 in ALL (Non-patent literature 1).

It is inferred that a MLL fusion protein fused with a fusion partnergene can cause unrestrained proliferation of undifferentiatedhematopoietic cells to lead to leukemia (Non-patent literature 2). It isreported that a MLL fusion protein firstly binds to menin to form acomplex. Accordingly, it is expected that canceration caused by a MLLfusion protein can be prevented by inhibiting the first binding betweena MLL fusion protein and menin (Non-patent literature 3).

It is reported that MLL acts as an activation cofactor of an androgensignal in prostate cancer. Accordingly, it is expected that a smallmolecular inhibitor which is targeted to inhibiting the binding betweenmenin and a MLL fusion protein is useful as a medicament for treatingthe cancer (Non-patent literature 4).

It is reported that menin acts as an activation cofactor of an estrogensignal in breast cancer. Accordingly, it is expected that a smallmolecular inhibitor which is targeted to inhibiting the binding betweenmenin and a MLL fusion protein is useful as a medicament of the cancer(Non-patent literature 5).

It is reported that menin or MLL is important for tumor progression inEwing's sarcoma, liver cancer, and p53 gain-of-function mutation cancer,and it is expected that a small molecular inhibitor which is targeted toinhibiting the binding between menin and a MLL fusion protein is usefulas a medicament of the cancers (Non-patent literature 6).

Patent literatures 1 to 3 disclose small molecular inhibitors which aretargeted to inhibiting the binding between menin and a MLL fusionprotein. The present compound of the following formula (1) which is anoptically active azabicyclo ring derivative, however, is not disclosedor suggested in them.

PRIOR ART Patent Reference

-   [Patent Literature 1] WO 2017/112768-   [Patent Literature 2] WO 2017/214367-   [Patent Literature 3] WO 2018/050686

Non-Patent Reference

-   [Non-patent Literature 1] Look A. T, Science, 278 (5340): 1059-1064    (1997)-   [Non-patent Literature 2] Yokoyama A, et al., Cell 123 (2): 207-18    (2005)-   [Non-patent Literature 3] Yokoyama A, et al., Cancer Cell. 14(1):    34-46 (2008)-   [Non-patent Literature 4] Malik, R. et al., Nature Medicine.    21(4):344-352 (2015)-   [Non-patent Literature 5] Imacho, H et al., Breast Cancer Res Treat.    122(2):395-407 (2010)-   [Non-patent Literature 6] Svoboda, L. K. et al., Oncotargrt. 8    (1):458-471 (2017)

SUMMARY OF INVENTION Technical Problem

The purpose of the present invention may be to provide a compound whichhas an antitumor effect by inhibiting the binding between a MLL (mixedlineage leukemia) fusion protein that is fused with AF4 or AF9, which isa representative fusion partner gene causing MLL leukemia, and menin.More preferably, the purpose of the present invention may be to providea compound which has an antitumor effect by inhibiting the bindingbetween menin and a MLL fusion protein, and which is expected to havehigh safety by having a gap between the concentration at which thecompound can inhibit cell proliferation and the concentration at whichthe compound can inhibit hERG current. In other words, the purpose ofthe present invention is to provide an antitumor medicament with hightherapeutic effect.

Solution to Problem

The present inventors have extensively studied to reach the abovepurpose, and then have found that a compound of the following formula(1) or a pharmaceutically acceptable salt thereof (hereinafter, it maybe referred to as “the present compound”) has an excellent antitumoreffect through a potent inhibitory effect on the binding between meninand a MLL fusion protein.

Accordingly, the present invention is described as follows:

(Item 1)

A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³ and R⁴ are each independently hydrogen atom, halogen atom,cyano, nitro, carboxyl, sulfonic acid, —OR⁷, —SR⁷, —COR⁸, —CO₂R⁸,—CONR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, —OCOR⁸, —OCO₉R⁸, —OCONR⁹R¹⁰, —NR⁹R¹⁰,—NR¹¹COR⁸, —NR¹¹CO₀R⁸, —NR¹¹CONR⁹R¹⁰, —NR¹¹SO₂R⁸, —NR¹¹SO₂NR⁹R¹⁰, or-M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O, ═CR^(12A)R^(13A), ═N—NR^(12B)R^(13B), or═N—OR^(12B).

M is, each independently if there are plural, optionally-substitutedC₁₋₆ alkylene, optionally-substituted C₂₋₆ alkenylene,optionally-substituted C₂₋₆ alkynylene, optionally-substituted C₃₋₁₀cycloalkylene, optionally-substituted 3- to 10-membered saturatedheterocyclyl, optionally-substituted C₆₋₁₀ arylene, oroptionally-substituted 5- to 12-membered heteroarylene;

Q is, each independently if there are plural, hydrogen atom,optionally-substituted C₃₋₁₀ cycloalkyl, optionally-substituted 3- to10-membered saturated heterocyclyl, optionally-substituted C₆₋₁₀ aryl,or optionally-substituted 5- to 12-membered heteroaryl;

R⁷ is, each independently if there are plural, hydrogen atom,optionally-substituted C₁₋₆ alkyl, optionally-substituted C₂₋₆ alkenyl,optionally-substituted C₂₋₆ alkynyl, optionally-substituted C₃₋₁₀cycloalkyl, optionally-substituted 3- to 10-membered saturatedheterocyclyl, optionally-substituted C₆₋₁₀ aryl, oroptionally-substituted 5- to 12-membered heteroaryl;

R⁸ is, each independently if there are plural, C₁₋₆ alkyl;

R⁹, R¹⁰, and R¹¹ are each independently hydrogen atom or C₁₋₆ alkyl, andif there are plural R⁹, R¹⁰, or R¹¹, each R⁹, R¹⁰, or R¹¹ may be thesame or different, or when R⁹ and R¹⁰ are both C₁₋₆ alkyl, they may becombined with the nitrogen atom to which they are each attached to form3- to 8-membered nitrogen-containing saturated heterocycle;

R^(12A) and R^(13A) are each independently hydrogen atom, halogen atom,cyano, nitro, carboxyl, sulfonic acid, —COR¹⁴, —CO₂R¹⁴, —CONR¹⁵R¹⁶,—SO₂R¹⁴, —SO₂NR¹⁵R¹⁶, optionally-substituted C₁₋₆ alkyl,optionally-substituted C₂₋₆ alkenyl, optionally-substituted C₂₋₆alkynyl, optionally-substituted C₃₋₁₀ cycloalkyl, optionally-substituted3- to 10-membered saturated heterocyclyl, optionally-substituted C₆₋₁₀aryl, or optionally-substituted 5- to 12-membered heteroaryl, and ifthere are plural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be thesame or different, or when R^(12A) and R^(13A) are bothoptionally-substituted C₁₋₆ alkyl, they may be combined with the carbonatom to which they are attached to form 3- to 8-membered saturatedcarbocycle;

R^(12B) and R^(13B) are each independently hydrogen atom,optionally-substituted C₁₋₆ alkyl, optionally-substituted C₂₋₆ alkenyl,optionally-substituted C₂₋₆ alkynyl, optionally-substituted C₃₋₁₀cycloalkyl, optionally-substituted 3- to 10-membered saturatedheterocyclyl, optionally-substituted C₆₋₁₀ aryl, oroptionally-substituted 5- to 12-membered heteroaryl, and if there areplural R^(12B) or R^(13B), each R^(12B) or R^(13B) may be the same ordifferent, or when R^(12B) and R^(13B) are both optionally-substitutedC₁₋₆ alkyl, they may be combined with the nitrogen atom to which theyare attached to form 3- to 8-membered nitrogen-containing saturatedheterocycle;

R¹⁴ is, each independently if there are plural, C₁₋₆ alkyl;

R¹⁵ and R¹⁶ are each independently hydrogen atom or C₁₋₆ alkyl, and ifthere are plural R¹⁵ or R¹⁶, each R¹⁵ or R¹⁶ may be the same ordifferent, or when R¹⁵ and R¹⁶ are both C₁₋₆ alkyl, they may be combinedwith the nitrogen atom to which they are each attached to form 3- to8-membered nitrogen-containing saturated heterocycle;

X is —C(O)— or C₁₋₆ alkylene;

a, b, c, and d are each independently 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen atom, halogen atom, cyano, nitro, carboxyl,sulfonic acid, —OR¹⁷, —SR¹⁷, —COR¹⁸, —CO₂R¹⁸, —CONR¹⁹R²⁰, —SO₂R¹⁸,—SO₂NR¹⁹R²⁰, —OCOR¹⁸, —OCO²R¹⁸, —OCONR¹⁹R²⁰, —NR¹⁹R²⁰, —NR²¹COR¹⁸,—NR²¹CO₂R¹⁸, —NR²¹CONR¹⁹R²⁰, —NR²¹SO₂R¹⁸, —NR²¹SO₂NR¹⁹R²⁰,optionally-substituted C₁₋₆ alkyl, optionally-substituted C₂₋₆ alkenyl,or optionally-substituted C₂₋₆ alkynyl;

R¹⁷, R¹⁹, R²⁰, and R²¹ are each independently hydrogen atom or C₁₋₆alkyl, and if there are plural R¹⁷, R¹⁹, R²⁰, or R²¹, each R¹⁷, R¹⁹,R²⁰, or R²¹ may be the same or different, or when R¹⁹ and R²⁰ are bothC₁₋₆ alkyl, they may be combined with the nitrogen atom to which theyare each attached to form 3- to 8-membered nitrogen-containing saturatedheterocycle;

R¹⁸ is, each independently if there are plural, C₁₋₆ alkyl;

U is CR²² or nitrogen atom;

R²² is hydrogen atom, halogen atom, C₁₋₃ alkyl (which may be substitutedwith 1 to 5 the same or different substituents selected from fluorineatom, —OR²³ and —NR²³R²⁴), —CO₂R²⁵, —CONR²⁶R²⁷, or cyano;

R²³ and R²⁴ are each independently hydrogen atom or C₁₋₆ alkyl, and ifthere are plural R²³ or R²⁴, each R²³ or R²⁴ may be the same ordifferent, or when R²³ and R²⁴ are both C₁₋₆ alkyl, they may be combinedwith the nitrogen atom to which they are attached to form 3- to8-membered nitrogen-containing saturated heterocycle;

R²⁵ is C₁₋₆ alkyl;

R²⁶ and R²⁷ are each independently hydrogen atom or C₁₋₆ alkyl, or whenR²⁶ and R²⁷ are both C₁₋₆ alkyl, they may be combined with the nitrogenatom to which they are attached to form 3- to 8-memberednitrogen-containing saturated heterocycle;

Y is —O—, —S—, —CR²⁸R²⁹—, or —NR²⁸—;

R²⁸ and R²⁹ are each independently hydrogen atom or C₁₋₆ alkyl;

Z is hydrogen atom, halogen atom, cyano, nitro, carboxyl, sulfonic acid,—OR³⁰, —SR³⁰, —COR³¹, —CO₂R³¹, —CONR³²R³³, —SO₂R³¹, —SO₂NR³²R³³,—OCOR³¹, —OCO₂R³¹, —OCONR³²R³³, —NR³²R³³, —NR³⁴COR³¹, —NR³⁴CO₂R³¹,—NR³⁴CONR³²R³³, —NR³⁴SO₂R³¹, —NR³⁴SO₂NR³²R³³, optionally-substitutedC₁₋₆ alkyl, optionally-substituted C₂₋₆ alkenyl, optionally-substitutedC₂₋₆ alkynyl, optionally-substituted C₃₋₁₀ cycloalkyl,optionally-substituted 3- to 10-membered saturated heterocyclyl,optionally-substituted C₆₋₁₀ aryl, or optionally-substituted 5- to12-membered heteroaryl;

R³⁰, R³², R³³, and R³⁴ are each independently hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom, chlorine atom,bromine atom and hydroxy), or C₃₋₁₀ cycloalkyl, or when R³² and R³³ areboth C₁₋₆ alkyl, they may be combined with the nitrogen atom to whichthey are attached to form 3- to 8-membered nitrogen-containing saturatedheterocycle; and

R³¹ is C₁₋₆ alkyl optionally-substituted with 1 to 5 the same ordifferent substituents selected from the group consisting of fluorineatom, chlorine atom, bromine atom, and hydroxy.

(Item 2)

The compound of Item 1 or a pharmaceutically acceptable salt thereof,wherein

R¹, R², R³, and R⁴ are each independently hydrogen atom, halogen atom,—OR⁷, or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together toform each independently ═O or ═CR^(12A)R^(13A); and

R^(12A) and R^(13A) are each independently hydrogen atom, halogen atom,cyano, optionally-substituted C₁₋₆ alkyl, optionally-substituted C₂₋₆alkenyl, optionally-substituted C₂₋₆ alkynyl, optionally-substitutedC₃₋₁₀ cycloalkyl, optionally-substituted 3- to 10-membered saturatedheterocyclyl, optionally-substituted C₆₋₁₀ aryl oroptionally-substituted 5- to 12-membered heteroaryl, and if there areplural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be the same ordifferent, or when R^(12A) and R^(13A) are both optionally-substitutedC₁₋₆ alkyl, they may be combined with the carbon atom to which they areattached to form 3- to 8-membered saturated carbocycle.

(Item 3)

The compound of Item 1 or 2 or a pharmaceutically acceptable saltthereof, wherein

the optionally-substituted C₁₋₆ alkylene, the optionally-substitutedC₂₋₆ alkenylene, the optionally-substituted C₂₋₆ alkynylene, theoptionally-substituted C₃₋₁₀ cycloalkylene, the optionally-substituted3- to 10-membered saturated heterocyclyl, the optionally-substitutedC₆₋₁₀ arylene, the optionally-substituted 5- to 12-memberedheteroarylene, the optionally-substituted C₁₋₆ alkyl, theoptionally-substituted C₂₋₆ alkenyl, the optionally-substituted C₂₋₆alkynyl, the optionally-substituted C₃₋₁₀ cycloalkyl, theoptionally-substituted C₆₋₁₀ aryl, and the optionally-substituted 5- to12-membered heteroaryl in M, Q, Z, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), R⁷, R^(12A), R^(12B), R^(13A), and R^(13B) may beindependently substituted with 1 to 5 the same or different substituentsselected from the group consisting of

(1) halogen atom,

(2) hydroxy,

(3) C₆₋₁₀ aryl,

(4) 5- to 12-membered heteroaryl,

(5) C₁₋₆ alkyl,

(6) C₂₋₆ alkenyl,

(7) C₂₋₆ alkynyl,

(8) C₁₋₆ alkoxy,

(9) C₃₋₁₀ cycloalkyl,

(10) 3- to 10-membered saturated heterocyclyl,

(11) carboxyl,

(12) —COR^(35A),

(13) —CO₂R^(35A),

(14) —CONR^(36A)R^(37A),

(15) —NR^(36A)R^(37A),

(16) —NR^(36A)COR^(35A),

(17) —NR^(36A)SO₂R^(35A),

(18) —SO₂R^(35A),

(19) —SO₂NR^(36A)R^(37A),

(20) sulfonic acid,

(21) phosphoric acid,

(22) cyano, and

(23) nitro

wherein the said (3) C₆₋₁₀ aryl, (4) 5- to 12-membered heteroaryl, (5)C₁₋₆ alkyl, (6) C₂₋₆ alkenyl, (7) C₂₋₆ alkynyl, (8) C₁₋₆ alkoxy, (9)C₃₋₁₀ cycloalkyl, and (10) 3- to 10-membered saturated heterocyclyl maybe independently substituted with 1 to 5 the same or differentsubstituents selected from the group consisting of

(a) halogen atom,

(b) hydroxy,

(c) C₆₋₁₀ aryl,

(d) 5- to 10-membered heteroaryl,

(e) C₁₋₆ alkyl,

(f) C₂₋₆ alkenyl,

(g) C₂₋₆ alkynyl,

(h) C₁₋₆ alkoxy,

(i) C₃₋₁₀ cycloalkyl,

(j) 3- to 10-membered saturated heterocyclyl,

(k) carboxyl,

(l) —COR^(35B),

(m) —CO₂R^(35B),

(n) —CONR^(36B)R^(37B),

(o) —NR^(36B)R^(37B),

(p) —NR^(36B)COR^(35B),

(q) —NR^(36B)SO₂R^(35B),

(r) —SO₂R^(35B),

(s) —SO₂NR^(36B)R^(37B),

(t) sulfonic acid,

(u) phosphoric acid,

(v) cyano, and

(w) nitro;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 8-membered nitrogen-containing saturatedheterocycle;

R^(35B) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36B) and R^(37B) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36B) or R^(37B), each R^(36B) or R^(37B) maybe the same or different, or when R^(36B) and R^(37B) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 8-membered nitrogen-containing saturatedheterocycle.

(Item 4)

The compound of any one of Items 1 to 3 or a pharmaceutically acceptablesalt thereof, wherein

the optionally-substituted C₁₋₆ alkylene, the optionally-substitutedC₂₋₆ alkenylene, the optionally-substituted C₂₋₆ alkynylene, theoptionally-substituted C₃₋₁₀ cycloalkylene, the optionally-substituted3- to 10-membered saturated heterocyclyl, the optionally-substitutedC₆₋₁₀ arylene, the optionally-substituted 5- to 12-memberedheteroarylene, the optionally-substituted C₁₋₆ alkyl, theoptionally-substituted C₂₋₆ alkenyl, the optionally-substituted C₂₋₆alkynyl, the optionally-substituted C₃₋₁₀ cycloalkyl, theoptionally-substituted C₆₋₁₀ aryl, and the optionally-substituted 5- to12-membered heteroaryl in M, Q, Z, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), R⁷, R^(12A), R^(12B), R^(13A), and R^(13B) may beindependently substituted with 1 to 5 the same or different substituentsselected from the group consisting of:

(1) halogen atom,

(2) hydroxy,

(3) phenyl,

(4) 5- to 6-membered heteroaryl,

(5) C₁₋₆ alkyl optionally-substituted with 1 to 3 hydroxy,

(6) C₂₋₆ alkynyl,

(7) C₁₋₆ alkoxy,

(8) C₃₋₇ cycloalkyl,

(9) 3- to 7-membered saturated heterocyclyl,

(10) —COR^(35A),

(11) —CO₂R^(3A),

(12) —CONR^(36A)R^(37A),

(13) —NR^(36A)R^(37A),

(14) —NR^(36A)COR^(35A),

(15) —NR^(36A)SO₂R^(35A),

(16) —SO₂R^(35A),

(17) —SO₂NR^(36A)R^(37A),

(18) cyano, and

(19) nitro;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 5)

The compound of any one of Items 1 to 4 or a pharmaceutically acceptablesalt thereof, wherein

X is —C(O)—; and

Y is —O—.

(Item 6)

The compound of any one of Items 1 to 5 or a pharmaceutically acceptablesalt thereof, wherein

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom; and

R^(6C) is fluorine atom.

(Item 7)

The compound of any one of Items 1 to 6 or a pharmaceutically acceptablesalt thereof, wherein

U is CR²² or nitrogen atom; and

R²² is —CF₃ or cyano.

(Item 8)

The compound of any one of Items 1 to 7 or a pharmaceutically acceptablesalt thereof, wherein

U is nitrogen atom.

(Item 9)

The compound of any one of Items 1 to 8 or a pharmaceutically acceptablesalt thereof, wherein

Z is —CONR³²R³³, 3- to 6-membered saturated heterocyclyl (which may besubstituted with 1 to 3 the same or different substituents selected fromC₁₋₃ alkyl and C₃₋₆ cycloalkyl), phenyl (which may be substituted with 1to 3 the same or different substituents selected from cyano, C₁₋₃ alkyl,and C₃₋₆ cycloalkyl, wherein the alkyl or the cycloalkyl may besubstituted with 1 to 3 hydroxy), or 5- to 6-membered heteroaryloptionally-substituted with 1 to 3 C₁₋₃ alkyl; and

R³² and R³³ are each independently hydrogen atom or C₁₋₃ alkyl, or whenR³² and R³³ are both C₁₋₆ alkyl, they may be combined with the nitrogenatom to which they are attached to form 3- to 6-memberednitrogen-containing saturated heterocycle.

(Item 10)

The compound of any one of Items 1 to 9 or a pharmaceutically acceptablesalt thereof, wherein

Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6),(Z-7), (Z-8), or (Z-9):

wherein * is a bonding site to the aromatic ring.

(Item 11)

The compound of Item 10 or a pharmaceutically acceptable salt thereof,wherein

Z is (Z-3).

(Item 12)

The compound of any one of Items 1 to 11 or a pharmaceuticallyacceptable salt thereof, wherein

M is, each independently if there are plural, C₁₋₆ alkylene (which maybe substituted with 1 to 5 the same or different substituents selectedfrom the group consisting of fluorine atom, chlorine atom, bromine atom,hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A) and cyano), C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₁₀cycloalkylene, 3- to 10-membered saturated heterocyclyl, C₆₋₁₀ arylene,or 5- to 12-membered heteroarylene, wherein the alkenylene, thealkynylene, the cycloalkylene, the saturated heterocyclyl, the aryleneand the heteroarylene may be each independently substituted with 1 to 5the same or different substituents selected from the group consisting offluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

Q is, each independently if there are plural, hydrogen atom, C₃₋₁₀cycloalkyl, 3- to 10-membered saturated heterocyclyl, C₆₋₁₀ aryl, or 5-to 12-membered heteroaryl, wherein the cycloalkyl, the saturatedheterocyclyl, the aryl, and the heteroaryl may be each independentlysubstituted with 1 to 5 the same or different substituents selected fromthe group consisting of fluorine atom, chlorine atom, bromine atom,hydroxy, C₁₋₃ alkyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R⁷ is, each independently if there are plural, hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom, chlorine atom,bromine atom, hydroxy, phenyl, 5- to 6-membered heteroaryl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered saturated heterocyclyl, C₁₋₃alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 3- to 10-membered saturatedheterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl, wherein thealkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to5 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, halogen atom,cyano, C₁₋₆ alkyl (which may be substituted with 1 to 5 the same ordifferent substituents selected from the group consisting of fluorineatom, chlorine atom, bromine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy,—CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 3- to 10-membered saturatedheterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl, wherein thealkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to5 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₇NR^(36A)R^(37A) and cyano, and if there are plural R^(12A) orR^(13A), each R^(12A) or R^(13A) may be the same or different, or whenR^(12A) and R^(13A) are both C₁₋₆ alkyl, they may be combined with thecarbon atom to which they are attached to form 3- to 8-memberedsaturated carbocycle;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁_alkyl,they may be combined with the same nitrogen atom to which they areattached to form 3- to 8-membered nitrogen-containing saturatedheterocycle.

(Item 13)

The compound of Item 1 of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, halogen atom,—OR⁷, or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined to formeach independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₆ alkylene (which maybe substituted with 1 to 5 the same or different substituents selectedfrom the group consisting of fluorine atom, chlorine atom, bromine atom,hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano), C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₁₀cycloalkylene, 3- to 10-membered saturated heterocyclyl, C₆₋₁₀ arylene,or 5- to 12-membered heteroarylene, wherein the alkenylene, thealkynylene, the cycloalkylene, the saturated heterocyclyl, the arylene,and the heteroarylene may be each independently substituted with 1 to 5the same or different substituents selected from the group consisting offluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

Q is, each independently if there are plural, hydrogen atom, C₃₋₁₀cycloalkyl, 3- to 10-membered saturated heterocyclyl, C₆₋₁₀ aryl or 5-to 12-membered heteroaryl, wherein the cycloalkyl, the saturatedheterocyclyl, the aryl and the heteroaryl may be each independentlysubstituted with 1 to 5 the same or different substituents selected fromthe group consisting of fluorine atom, chlorine atom, bromine atom,hydroxy, C₁₋₃ alkyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R⁷ is, each independently if there are plural, hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom, chlorine atom,bromine atom, hydroxy, phenyl, 5- to 6-membered heteroaryl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, 3- to 7-membered saturated heterocyclyl, C₁₋₃alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 3- to 10-membered saturatedheterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl, wherein thealkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to5 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(30A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, halogen atom,C₁₋₆ alkyl (which may be substituted with 1 to 5 the same or differentsubstituents selected from the group consisting of fluorine atom,chlorine atom, bromine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy,—CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 3- to 10-membered saturatedheterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl, wherein thealkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to5 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(3A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano, and if there are plural R^(12A) orR^(13A), each R^(12A) or R^(13A) may be the same or different, or whenR^(12A) and R^(13A) are both C₁₋₆ alkyl, they may be combined with thecarbon atom to which they are attached to form 3- to 8-memberedsaturated carbocycle;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle; and

a, b, c, and d are each independently 1 or 2.

(Item 14)

The compound of any one of Items 1 to 13 or a pharmaceuticallyacceptable salt thereof, wherein

M is, each independently if there are plural, C₁₋₆ alkylene which may besubstituted with 1 to 5 the same or different substituents selected fromthe group consisting of fluorine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

[Item 15]

The compound of any one of Items 1 to 14 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₁₀ cycloalkyl, 3- to10-membered saturated heterocyclyl, C₆₋₁₀ aryl, or 5- to 12-memberedheteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to5 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A) and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 16)

The compound of any one of Items 1 to 15 or a pharmaceuticallyacceptable salt thereof, wherein

R⁷ is, each independently if there are plural, hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom, phenyl, C₃₋₇cycloalkyl, and 3- to 7-membered saturated heterocyclyl), C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 3- to 10-membered saturated heterocyclyl(wherein the cycloalkyl and the saturated heterocyclyl may be eachindependently substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom and C₁₋₃ alkyl),C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl (wherein the aryl and theheteroaryl may be each independently substituted with 1 to 5 the same ordifferent substituents selected from the group consisting of fluorineatom, chlorine atom, bromine atom, and C₁₋₃ alkyl).

(Item 17)

The compound of any one of Items 1 to 16 or a pharmaceuticallyacceptable salt thereof, wherein

R⁷ is, each independently if there are plural, hydrogen atom, C₁₋₆alkyl, or C₂₋₆ alkenyl, wherein the alkyl or the alkenyl may besubstituted with one phenyl.

(Item 18)

The compound of any one of Items 1 to 17 or a pharmaceuticallyacceptable salt thereof, wherein

R^(12A) and R^(13A) are each independently hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 5 the same or different substituentsselected from the group consisting of fluorine atom, chlorine atom,bromine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A) and cyano), C₃₋₁₀ cycloalkyl, 3- to 10-memberedsaturated heterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl,wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and theheteroaryl may be each independently substituted with 1 to 5 the same ordifferent substituents selected from the group consisting of fluorineatom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄ alkynyl,C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A) and cyano, and ifthere are plural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be thesame or different, or when R^(12A) and R^(13A) are both C₁₋₆ alkyl, theymay be combined with the carbon atom to which they are each attached toform 3- to 8-membered saturated carbocycle;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 19)

The compound of any one of Items 1 to 18 or a pharmaceuticallyacceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, halogen atom,—OR⁷, or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together toform each independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₆ alkylene which may besubstituted with 1 to 3 the same or different substituents selected fromthe group consisting of fluorine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(35A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(36A)R^(37A) and cyano;

Q is, each independently if there are plural, C₃₋₁₀ cycloalkyl, 3- to10-membered saturated heterocyclyl, C₆₋₁₀ aryl or 5- to 12-memberedheteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, thearyl, and the heteroaryl may be each independently substituted with 1 to3 the same or different substituents selected from the group consistingof fluorine atom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R⁷ is, each independently if there are plural, hydrogen atom, C₁₋₆alkyl, or C₂₋₆ alkenyl, wherein the alkyl and the alkenyl may besubstituted with one phenyl;

R^(12A) and R^(13A) are each independently hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 3 the same or different substituentsselected from the group consisting of fluorine atom, chlorine atom,bromine atom, hydroxy, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A),—NR^(36A)R^(37A), —NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano), C₃₋₁₀ cycloalkyl, 3- to 10-memberedsaturated heterocyclyl, C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl,wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and theheteroaryl may be each independently substituted with 1 to 3 the same ordifferent substituents selected from the group consisting of fluorineatom, chlorine atom, bromine atom, hydroxy, C₁₋₃ alkyl, C₂₋₄ alkynyl,C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A), —NR^(36A)COR^(37A),—NR^(36A)SO₂R^(35A), —SO₂R^(35A), —SO₂NR^(37A)R^(37A), and cyano, and ifthere are plural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be thesame or different, or when R^(12A) and R^(13A) are both C₁₋₆ alkyl, theymay be combined with the carbon atom to which they are attached to form3- to 8-membered saturated carbocycle;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁_alkyl,they may be combined with the nitrogen atom to which they are attachedto form 3- to 6-membered nitrogen-containing saturated heterocycle; and

a, b, c and d are each independently 1 or 2.

(Item 20)

The compound of any one of Items 1 to 19 or a pharmaceuticallyacceptable salt thereof, wherein

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O or ═CR^(12A)R^(13A).

(Item 21)

The compound of any one of Items 1 to 20 or a pharmaceuticallyacceptable salt thereof, wherein

M is, each independently if there are plural, C₁₋₃ alkylene which may besubstituted with 1 to 3 the same or different substituents selected fromthe group consisting of fluorine atom, C₂₋₄ alkynyl, C₁₋₃ alkoxy,—NR^(36A)R^(37A), and cyano; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 22)

The compound of any one of Items 1 to 21 or a pharmaceuticallyacceptable salt thereof, wherein

M is, each independently if there are plural, C₁₋₃ alkylene.

(Item 23)

The compound of any one of Items 1 to 22 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₆ cycloalkyl, 3- to6-membered saturated heterocyclyl, phenyl, or 5- to 6-memberedheteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, thephenyl, and the heteroaryl may be each independently substituted with 1to 3 the same or different substituents selected from the groupconsisting of fluorine atom, chlorine atom, bromine atom, C₁₋₃ alkyl,C₂₋₄ alkynyl, C₁₋₃ alkoxy, —CONR^(36A)R^(37A), —NR^(36A)R^(37A),—NR^(36A)COR^(35A), —NR^(36A)SO₂R^(35A), —SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 24)

The compound of any one of Items 1 to 23 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₆ cycloalkyl, 3- to6-membered saturated heterocyclyl, phenyl or 5- to 6-memberedheteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, thephenyl, and the heteroaryl may be each independently substituted with 1to 3 the same or different substituents selected from the groupconsisting of fluorine atom, C₁₋₃ alkyl, —NR^(36A)SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 25)

The compound of any one of Items 1 to 24 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano.

(Item 26)

The compound of any one of Items 1 to 25 or a pharmaceuticallyacceptable salt thereof, wherein

R^(12A) and R^(13A) are each independently hydrogen atom, C₁₋₆ alkyl(which may be substituted with 1 to 3 the same or different substituentsselected from the group consisting of fluorine atom,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano), C₃₋₁₀ cycloalkyl(which may be substituted with 1 to 3 the same or different substituentsselected from the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A) and cyano), and if there areplural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be the same ordifferent, or when R^(12A) and R^(13A) are both C₁₋₃ alkyl, they may becombined with the carbon atom to which they are attached to form 3- to6-membered saturated carbocycle;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 27)

The compound of any one of Items 1 to 26 or a pharmaceuticallyacceptable salt thereof, wherein

R^(12A) and R^(13A) are each independently hydrogen atom, or C₃₋₆cycloalkyl which may be substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano, and if thereare plural R^(12A) and R^(13A), each R^(12A) and R^(13A) may be the sameor different;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl; and

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle.

(Item 28)

The compound of any one of Items 1 to 27 or a pharmaceuticallyacceptable salt thereof, wherein

a and c are 1; and

both b and d are either 1 or 2.

(Item 29)

The compound of any one of Items 1 to 28 or a pharmaceuticallyacceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³ and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₃ alkylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, C₃₋₆cycloalkyl which may be substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano, and if thereare plural R^(12A) or R^(13A), each R^(12A) or R^(13A) may be the sameor different,

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle;

a and c are 1; and

both b and d are either 1 or 2.

(Item 30)

The compound of any one of Items 1 to 29 or a pharmaceuticallyacceptable salt thereof, wherein

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═CR^(12A)R^(13A).

(Item 31)

The compound of any one of Items 1 to 30 or a pharmaceuticallyacceptable salt thereof, wherein

M is methylene.

(Item 32)

The compound of any one of Items 1 to 31 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom and C₁₋₃ alkyl.

(Item 33)

The compound of any one of Items 1 to 32 or a pharmaceuticallyacceptable salt thereof, wherein

Q is, each independently if there are plural, C₃₋₆ cycloalkyl.

(Item 34)

The compound of any one of Items 1 to 33 or a pharmaceuticallyacceptable salt thereof, wherein

R^(12A) and R^(13A) are each independently hydrogen atom or C₃₋₆cycloalkyl.

(Item 35)

The compound of any one of Items 1 to 34 or a pharmaceuticallyacceptable salt thereof, wherein

R^(12A) and R^(13A) are hydrogen atom.

(Item 36)

The compound of any one of Items 1 to 35 or a pharmaceuticallyacceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to form═CH₂;

M is, each independently if there are plural, methylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl;

a and c are 1; and

both b and d are either 1 or 2.

(Item 37)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ and R² are hydrogen atom; and

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

provided that both R³ and R⁴ are not hydrogen atom.

(Item 38)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ and R² are each independently hydrogen atom or -M-Q; and

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

provided that both R¹ and R² are not hydrogen atom.

(Item 39)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is hydrogen atom;

R² is -M-Q;

R³ is hydrogen atom; and

R⁴ is hydrogen atom or fluorine atom.

(Item 40)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is -M-Q;

R² is hydrogen atom;

R³ is hydrogen atom or fluorine atom; and

R⁴ is hydrogen atom.

(Item 41)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹, R², R³, and R⁴ are each independently hydrogen atom; or R¹ and R²and/or R³ and R⁴ may be combined together to form ═CH₂;

provided that all of R¹, R², R³ and R⁴ are not hydrogen atom.

(Item 42)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ and R² are combined together to form ═CH₂; and

R³ and R⁴ are hydrogen atom.

(Item 43)

The compound of any one of Items 1 to 36 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ and R² are hydrogen atom; and

R³ and R⁴ are combined together to form ═CH₂.

(Item 44)

The compound of any one of Items 1 to 43 or a pharmaceuticallyacceptable salt thereof, wherein

a, b, c, and d are 1.

(Item 45)

The compound of any one of Items 1 to 43 or a pharmaceuticallyacceptable salt thereof, wherein

a and c are 1; and

b and d are 2.

(Item 46)

The compound of any one of Items 1 to 45 or a pharmaceuticallyacceptable salt thereof, wherein

p is 1.

(Item 47)

The compound of any one of Items 1 to 45 or a pharmaceuticallyacceptable salt thereof, wherein

p is 2.

(Item 48)

The compound of Item 1 or a pharmaceutically acceptable salt thereof,selected from:

-   2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 1),-   2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 3),-   2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 4),-   2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 5),-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 6),-   5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 7),-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 8),-   5-fluoro-2-[(4-{6-[(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 9),-   5-fluoro-2-[(4-{6-[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 10),-   2-[(4-{6-[(1R,3S,4R)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 11),-   5-fluoro-2-[(4-{7-[(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 12),-   2-[(4-{7-[(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 14),-   2-[(4-{6-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 15),-   2-[(4-{7-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 16),-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 18),-   2-[(4-{7-[(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 19) and-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 20).

(Item 49)

The compound of Item 1 or a pharmaceutically acceptable salt thereof,selected from:

-   2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 1),-   2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 3),-   2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 4) and-   2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 5).

(Item 50)

The compound of Item 1, or a hydrochloride, L(+)-tartrate or succinatethereof, selected from:

-   2-[(4-{7-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 1),-   2-[(4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 3),-   2-[(4-{7-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 4) and-   2-[(4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 5).

(Item 51)

The compound of Item 1 or a pharmaceutically acceptable salt thereof,selected from:

-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 6),-   5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 7),-   2-[(4-{6-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 15),-   2-[(4-{7-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 16),-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 18) and-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 20).

(Item 52)

The compound of Item 1, or a hydrochloride, L(+)-tartrate or succinatethereof, selected from:

-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 6),-   5-fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 7),-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 18) and-   5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 20).

(Item 53)

-   2-[(4-{7-[(1S,3S,4R,6S)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 1), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 54)

-   2-[(4-{6-[(1S,3S,4R,6S)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 3), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 55)

-   2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 4), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 56)

-   2-[(4-{6-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide    (Example 5), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 57)

-   5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 6), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 58)

-   5-Fluoro-2-[(4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 7), or a hydrochloride, L(+)-tartrate or succinate thereof.

(Item 59)

-   5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 18), or a hydrochloride, L(+)-tartrate or succinate    thereof.

(Item 60)

-   5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide    (Example 20), or a hydrochloride, L(+)-tartrate or succinate    thereof.

(Item 61)

A medicament comprising the compound of any one of Items 1 to 60 or apharmaceutically acceptable salt thereof as an active ingredient.

(Item 62)

An antitumor medicament comprising the compound of any one of Items 1 to60 or a pharmaceutically acceptable salt thereof as an activeingredient.

(Item 63)

The antitumor medicament of Items 62, wherein the tumor is acuteleukemia (including MLL acute leukemia, MLL partial tandem duplicateacute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia,chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera,malignant lymphoma (including B-cell lymphoma), myeloma (includingmultiple myeloma), brain tumor, cancer of the head and neck, esophagealcancer, thyroid cancer, small cell lung cancer, non-small cell lungcancer, breast cancer, gastric cancer, gallbladder and bile duct cancer,liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer,rectal cancer, anal cancer, chorionepithelioma, endometrial cancer,cervical cancer, ovarian cancer, bladder cancer, urothelial cancer,renal cancer, renal cell cancer, prostate cancer, testicular tumor,testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor,malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma,chondrosarcoma, soft tissue sarcoma, or skin cancer.

(Item 64)

The antitumor medicament of Item 62 or 63, wherein the tumor is acuteleukemia (including MLL acute leukemia, MLL partial tandem duplicateacute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98acute leukemia, and CALM acute leukemia), chronic myeloid leukemia,malignant lymphoma (including B-cell lymphoma), myeloma (includingmultiple myeloma), brain tumor, prostate cancer, breast cancer,neuroblastoma, Ewing's sarcoma, or liver cancer.

(Item 65)

The antitumor medicament of any one of Items 62 to 64, wherein the tumoris MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPMmutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALMacute leukemia, chronic myeloid leukemia, B-cell lymphoma, multiplemyeloma, neuroblastoma, or prostate cancer.

(Item 66)

The antitumor medicament of any one of Items 62 to 65, wherein the tumoris MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPMmutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALMacute leukemia, chronic myeloid leukemia, B-cell lymphoma, or multiplemyeloma.

(Item 67)

The antitumor medicament of any one of Items 62 to 66, wherein the tumoris MLL acute leukemia, or NPM mutated acute leukemia.

(Item 68)

The antitumor medicament of any one of Items 62 to 67, wherein the tumoris accompanied by high expression of HOXa gene cluster, or MEIS genecluster.

(Item 69)

The antitumor medicament of any one of Items 62 to 68, wherein the tumoris accompanied by p53 gain-of-function mutation.

(Item 70)

A method for treating a tumor comprising administrating the compound ofany one of Items 1 to 60 or a pharmaceutically acceptable salt thereofto a patient in need thereof.

[Item 71]

The method of Item 70, wherein the tumor is involved in Menin-MLL.

(Item 72)

Use of the compound of any one of Items 1 to 60 or a pharmaceuticallyacceptable salt thereof in the manufacture of an antitumor medicament.

(Item 73)

The compound of any one of Items 1 to 60 or a pharmaceuticallyacceptable salt thereof for use in the treatment of a tumor.

(Item 74)

A pharmaceutical composition comprising the compound of any one of Items1 to 60 or a pharmaceutically acceptable salt thereof in combinationwith at least one different agent or a pharmaceutically acceptable saltthereof, wherein the different agent is at least one agent selected fromthe group consisting of an antitumor alkylating agent, an antitumorantimetabolite, an antitumor antibiotic, a plant-derived antitumormedicament, an antitumor platinum complex compound, an antitumorcamptothecin derivative, an antitumor tyrosine kinase inhibitor, anantitumor serine/threonine kinase inhibitor, an antitumor phospholipidkinase inhibitor, an antitumor monoclonal antibody, interferon, anbiological response modifier, a hormone preparation, an angiogenicinhibitor, an immune checkpoint inhibitor, an epigenetics-associatedmolecular inhibitor, a protein post-translational modificationinhibitor, a proteasome inhibitor, and other antitumor medicaments.

(Item 75)

The compound of any one of Items 1 to 60 or a pharmaceuticallyacceptable salt thereof for treating a tumor, which is used incombination with at least one different agent or a pharmaceuticallyacceptable salt thereof, wherein the different agent is at least oneagent selected from an antitumor alkylating agent, an antitumorantimetabolite, an antitumor antibiotic, a plant-derived antitumormedicament, an antitumor platinum complex compound, an antitumorcamptothecin derivative, an antitumor tyrosine kinase inhibitor, anantitumor serine/threonine kinase inhibitor, an antitumor phospholipidkinase inhibitor, an antitumor monoclonal antibody, interferon, abiological response modifier, a hormone preparation, an angiogenicinhibitor, an immune checkpoint inhibitor, an epigenetics-associatedmolecular inhibitor, a protein post-translational modificationinhibitor, a proteasome inhibitor, and other antitumor medicaments.

Effect of the Invention

The present invention provides an inhibitor of the binding between meninand MLL fusion protein, comprising an optically-active azabicyclo ringderivative or a pharmaceutically acceptable salt thereof. The compoundof the present invention is useful as a medicament for diseases involvedin the binding between menin and MLL, and is applicable to a patientsuffering from, specifically, MLL acute leukemia, NPM mutated acuteleukemia, prostate cancer, breast cancer, Ewing's sarcoma, liver cancer,p53 gain-of-function mutated cancer, and the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of crystal form I of thecompound of Example 21. The horizontal axis shows a diffraction angle 2θ(°) and the vertical axis shows counts (the same as in FIG. 2 to FIG.5).

FIG. 2 shows a powder X-ray diffraction pattern of crystal form II ofthe compound of Example 22.

FIG. 3 shows a powder X-ray diffraction pattern of crystal form III ofthe compound of Example 23.

FIG. 4 shows a powder X-ray diffraction pattern of crystal form IV ofthe compound of Example 24.

FIG. 5 shows a powder X-ray diffraction pattern of crystal form V of thecompound of Example 25.

DESCRIPTION OF EMBODIMENTS

Hereinafter, terms used herein are explained as follows.

The “halogen atom” includes, for example, fluorine atom, chlorine atom,bromine atom, iodine atom, and the like. It is preferably fluorine atom.

The “C₁₋₆ alkyl” means alkyl having 1 to 6 carbon atoms, and “C₆ alkyl”means alkyl having 6 carbon atoms. The same is applied to the case ofthe other carbon numbers.

The “C₁₋₆ alkyl” means straight or branched chain saturated hydrocarbongroup having 1 to 6 carbon atoms. The C₁₋₆ alkyl includes preferably“C₁₋₄ alkyl”, more preferably “C₁₋₃ alkyl”. The “C₁₋₃ alkyl” includes,for example, methyl, ethyl, propyl, 1-methylethyl, and the like. The“C₁₋₄ alkyl” includes, for example, butyl, 1,1-dimethylethyl,1-methylpropyl, 2-methylpropyl, and the like, besides the exampleslisted in the said “C₁₋₃ alkyl”. The “C₁₋₆ alkyl” includes, for example,pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl,2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, hexyl, and the like, besides the examples listed in thesaid “C₁₋₄ alkyl”.

The “C₂₋₆ alkenyl” means straight or branched chain unsaturatedhydrocarbon group having 2 to 6 carbon atoms and 1 to 3 double bonds.The “C₂₋₆ alkenyl” includes preferably “C₂₋₄ alkenyl”. The “C₂₋₄alkenyl” includes, for example, vinyl, propenyl, methylpropenyl,butenyl, and the like. The “C₂₋₆ alkenyl” includes, for example,pentenyl, hexenyl, and the like, besides the examples listed in the said“C₂₋₄ alkenyl”.

The “C₂₋₆ alkynyl” means straight or branched chain unsaturatedhydrocarbon group having 2 to 6 carbon atoms and a triple bond. The“C₂₋₆ alkynyl” includes preferably “C₂₋₄ alkynyl”. The “C₂₋₄ alkynyl”includes, for example, propynyl, methylpropynyl, butynyl, and the like.The “C₂₋₆ alkynyl” includes, for example, methylbutynyl, pentynyl,hexynyl, and the like, besides the examples listed in the said “C₂₋₄alkynyl”.

The “C₁₋₆ alkoxy” means “C₁₋₆ alkyloxy”, and the part “C₁₋₆ alkyl” is asdefined in the said “C₁₋₆ alkyl”. The “C₁₋₆ alkoxy” includes preferably“C₁₋₄ alkoxy”, more preferably “C₁₋₃ alkoxy”. The “C₁₋₃ alkoxy”includes, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, and thelike. The “C₁₋₄ alkoxy” includes, for example, butoxy,1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, and the like,besides the examples listed in the said “C₁₋₃ alkyl”. The “C₁₋₆ alkoxy”includes, for example, pentyloxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy,3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, andthe like, besides the examples listed in the said “C₁₋₄ alkyl”.

The “C₁₋₆ alkylene” means divalent straight or branched chain saturatedhydrocarbon group having 1 to 6 carbon atoms. The “C₁₋₆ alkylene”includes preferably “C₁₋₄ alkylene”, more preferably “C₁₋₃ alkylene”.The “C₁₋₃ alkylene” includes, for example, methylene, ethylene,propylene, trimethylene, and the like. The “C₁₋₄ alkylene” includes, forexample, butylene, 1,1-dimethylethylene, 1,2-dimethylethylene,1-methyltrimethylene, 2-methyltrimethylene, and the like, besides theexamples listed in the said “C₁₋₃ alkylene”. The “C₁₋₆ alkylene”includes, for example, pentylene, 1,1-dimethyltrimethylene,1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene,1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, andthe like, besides the examples listed in the said “C₁₋₄ alkylene”.

The “C₂₋₆ alkenylene” means divalent straight or branched chainunsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3double bonds. The “C₂₋₆ alkenylene” includes preferably “C₂₋₄alkenylene”. The “C₂₋₄ alkenylene” includes, for example, vinylene,propenylene, methylpropenylene, butenylene, and the like. The “C₂₋₆alkenylene” includes, for example, pentenylene, hexenylene, and thelike, besides the examples listed in the said “C₂₋₄ alkenyl”.

The “C₂₋₆ alkynylene” means divalent straight or branched chainunsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3triple bonds. The “C₂₋₆ alkynylene” includes preferably “C₂₋₄alkynylene”. The “C₂₋₄ alkynylene” includes, for example, ethynylene,propynylene, butynylene, and the like. The “C₂₋₆ alkynylene” includes,for example, methylbutynylene, pentynylene, hexynylene, and the like,besides the examples listed in the said “C₂₋₄ alkynylene”.

The “C₃₋₁₀ cycloalkyl” means cyclic saturated hydrocarbon group having 3to 10 carbon atoms, which may have a partially-unsaturated bond or abridged structure. The “C₃₋₁₀ cycloalkyl” includes preferably “C₃₋₇cycloalkyl”. The “C₃₋₇ cycloalkyl” includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The“C₃₋₁₀ cycloalkyl” includes, for example, cyclooctyl, cyclononyl,cyclodecyl, adamantyl, and the like, besides the examples listed in thesaid “C₃₋₇ cycloalkyl”.

The “C₃₋₁₀ cycloalkyl” also encompasses bicyclic compounds, i.e., C₃₋₁₀cycloalkyl fused with an aromatic hydrocarbon ring. The fused ringcompounds includes, for example, the following structures:

The “C₃₋₁₀ cycloalkylene” means divalent cyclic saturated hydrocarbongroup having 3 to 10 carbon atoms, which may have apartially-unsaturated bond or a bridged structure. The “C₃₋₁₀cycloalkylene” includes preferably “C₃₋₇ cycloalkylene”. The “C₃₋₇cycloalkylene” includes, for example, cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, cycloheptylene, and the like. The “C₃₋₁₀cycloalkylene” includes, for example, cyclooctylene, cyclononylene,cyclodecylene, adamantylene, and the like, besides the examples listedin the said “C₃₋₇ cycloalkylene”.

The “3- to 8-membered saturated carbocycle” means cyclic saturatedhydrocarbon group having 3 to 8 carbon atoms. The “3- to 8-memberedsaturated carbocycle” includes preferably “4- to 6-membered saturatedcarbocycle”. The “4- to 6-membered saturated carbocycle” includes, forexample, cyclobutane ring, cyclopentane ring, cyclohexane ring, and thelike. The “3- to 8-membered saturated carbocycle” includes, for example,cyclopropane ring, cycloheptane ring, cyclooctane ring, and the like,besides the examples listed in the said “4- to 6-membered saturatedcarbocycle”. The “3- to 10-membered saturated heterocyclyl” meansmonovalent or divalent saturated heterocycle consisting of 1 to 2 atomsselected independently from the group consisting of nitrogen atom,oxygen atom and sulfur atom, and 2 to 9 carbon atoms, which may have apartially-unsaturated bond and a bridged structure. The atoms of whichthe ring consists may include oxidized atoms such as —C(O)—, —S(O)—, and—SO₂—. The “3- to 10-membered saturated heterocyclyl” is preferably “4-to 7-membered monocyclic saturated heterocyclyl”, more preferably “5- or6-membered monocyclic saturated heterocyclyl”. The “5- or 6-memberedmonocyclic saturated heterocyclyl” includes, for example,tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl,oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl,oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofurylene,pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene,thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneiminylene,oxazolidinylene, thiazolidinylene, oxoimidazolidinylene,dioxoimidazolidinylene, oxooxazolidinylene, dioxooxazolidinylene,dioxothiazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, andthe like. The “4- to 7-membered monocyclic saturated heterocyclyl”includes, for example, oxetanyl, azetidinyl, oxetanylene, azetidinylene,and the like, besides the examples listed in the said “5- or 6-memberedmonocyclic saturated heterocyclyl”. The “3- to 10-membered saturatedheterocyclyl” includes, for example, oxiranyl, aziridinyl, oxiranylene,aziridinylene, and the like, besides the examples listed in the said “4-to 7-membered monocyclic saturated heterocyclyl”.

The “3- to 10-membered saturated heterocyclyl” also encompasses bicycliccompounds, i.e., “3- to 10-membered saturated heterocyclyl” fused with a6-membered aromatic hydrocarbon ring or a 6-membered aromaticheterocycle. The 6-membered aromatic hydrocarbon ring in the fused ringincludes benzene ring and the like. The 6-membered aromatic heterocyclein the fused ring includes pyridine, pyrimidine, pyridazine, and thelike. The bicyclic “3- to 10-membered saturated heterocyclyl” includesdihydroindolyl, dihydroisoindolyl, dihydropurinyl,dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl,dihydroindolylene, dihydroisoindolylene, dihydropurinylene,dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindolylene,indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene,tetrahydronaphthyridinylene, and the like.

The “3- to 8-membered nitrogen-containing saturated heterocycle” means asaturated heterocycle which consists of a nitrogen atom and 2 to 7carbon atoms. The “3- to 8-membered nitrogen-containing saturatedheterocycle” includes preferably “4- to 6-membered nitrogen-containingsaturated heterocycle”. The “4- to 6-membered nitrogen-containingsaturated heterocycle” includes, for example, azetidine ring,pyrrolidine ring, piperidine ring, and the like. The “3- to 8-memberednitrogen-containing saturated heterocycle” includes, for example,aziridine ring, azepane ring, azocane ring, and the like, besides theexamples listed in the said “4- to 6-membered nitrogen-containingsaturated heterocycle”.

The “C₆₋₁₀ aryl” means aromatic hydrocarbon ring having 6 to 10 carbonatoms. The “C₆₋₁₀ aryl” includes, for example, phenyl, 1-naphthyl,2-naphthyl, and the like. It includes preferably phenyl.

The “C₆₋₁₀ aryl” also encompasses bicyclic compounds, i.e., C₆₋₁₀ arylfused with C₄₋₆ cycloalkyl or 5- or 6-membered saturated heterocycle.The bicyclic “C₆₋₁₀ aryl” includes, for example, the following groups:

The “C₆₋₁₀ arylene” means divalent aromatic hydrocarbon group having 6to 10 carbon atoms. The “C₆₋₁₀ arylene” includes, for example,phenylene, 1-naphthylene, 2-naphthylene, and the like. It includespreferably phenylene.

The “aromatic hydrocarbon ring” means a cyclic part of the said “C₆₋₁₀aryl” and the said “C₆₋₁₀ arylene”.

The “5- to 12-membered heteroaryl” means monocyclic 5- to 7-memberedaromatic heterocyclic group or bicyclic 8- to 12-membered aromaticheterocyclic group having 1 to 4 atoms selected independently from thegroup consisting of nitrogen atom, oxygen atom and sulfur atom. It ispreferably “5- to 7-membered monocyclic heteroaryl”. It is morepreferably pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. It is evenmore preferably pyridyl. The “5- to 7-membered monocyclic heteroaryl”includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl,furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl,pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl,oxadiazolyl, triazolyl, tetrazolyl, and the like. The “5- to 12-memberedheteroaryl” includes indolyl, indazolyl, chromenyl, quinolyl,isoquinolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl,benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzoimidazolyl, andthe like, besides the examples listed in the said “5- to 7-memberedmonocyclic heteroaryl”.

The “5- to 12-membered heteroarylene” means divalent monocyclic 5- to7-membered aromatic heterocyclic group or divalent bicyclic 8- to12-membered aromatic heterocyclic group having 1 to 4 atoms selectedindependently from the group consisting of nitrogen atom, oxygen atomand sulfur atom. It is preferably “5- to 7-membered monocyclicheteroarylene”. It is more preferably pyridylene, pyrimidylene,quinolylene, or isoquinolylene. It is even more preferably pyridylene.The “5- to 7-membered monocyclic heteroarylene” includes, for example,pyridylene, pyridazinylene, isothiazolylene, pyrrolylene, furylene,thienylene, thiazolylene, imidazolylene, pyrimidinylene,thiadiazolylene, pyrazolylene, oxazolylene, isooxazolylene,pyrazinilene, triazinylene, triazolylene, oxadiazolylene, triazolylene,tetrazolylene, and the like. The “5- to 12-membered heteroarylene”includes indolylene, indazolylene, chromenylene, quinolylene,isoquinolylene, benzofuranylene, benzothienylene, benzooxazolylene,benzothiazolylene, benzoisooxazolylene, benzoisothiazolylene,benzotriazolylene, benzoimidazolylene, and the like, besides theexamples listed in the said “5- to 7-membered monocyclic heteroarylene”.

The “aromatic heterocyclic group” means a cyclic part of the said “5- to12-membered heteroaryl” and the said “5- to 12-membered heteroarylene”.

In the present specification, a bond across a ring group as showed inthe following formula (W) means that the bond is attached to asubstituable position of the “group”. For example, in the case of thefollowing formula (W):

it represents the following formula (W-1), (W-2), or (W-3):

In the present specification, the stereochemistry of substituents in thecompound of formula (I) or the example compounds can be illustrated, forexample, as follows:

In the above structure, the bonds shown as wedged line representsubstituents in front of the page; the bond shown as dashed linerepresents a substituent in back of the page; and the bond shown as wavyline represents that the substituent exists in front and back of thepage in an certain ratio, and when a bond which extends from the ringoutside is shown as linear line, it represents that the bond existseither in front or back of the page.

The “cancer” and “tumor” are used interchangeably, and the both meanmalignant neoplasm, which encompasses cancer, sarcoma, and hematologicmalignancy. The “cancer” and “tumor” include, for example, acuteleukemia (including MLL acute leukemia, MLL partial tandem duplicateacute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia,chronic myeloid leukemia, a myelodysplastic syndrome, polycythemia vera,malignant lymphoma (including B-cell lymphoma), myeloma (includingmultiple myeloma), brain tumor, cancer of the head and neck, esophagealcancer, thyroid cancer, small cell lung cancer, non-small cell lungcancer, breast cancer, gastric cancer, gallbladder and bile duct cancer,liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer,rectal cancer, anal cancer, chorionepithelioma, endometrial cancer,cervical cancer, ovarian cancer, bladder cancer, urothelial cancer,renal cancer, renal cell cancer, prostate cancer, testicular tumor,testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor,malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma,chondrosarcoma, soft tissue sarcoma, skin cancer, and the like. Theabove tumors may be accompanied by increased expression or mutation ofspecific genes. The tumors accompanied by increased expression of genesinclude, for example, tumors accompanied by high expression of HOXa genecluster, tumors accompanied by high expression of MEIS gene cluster, andthe like. The tumors accompanied by mutation of genes include tumorsaccompanied by p53 gain-of-function mutation and the like.

In the present compound of formula (1), preferred p, X, Y, Z, M, Q, a,b, c, d, U, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B), R^(6C),R^(6D), R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(12A), R^(12B), R^(13A), R^(13B), R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R^(35A), R^(35B), R^(36A), R^(36B),R^(37A) and R^(37B) are as follows, but the technical scope of thepresent invention is not limited to the scope of compounds listed below.

In an embodiment, p includes 1. In another embodiment, p includes 2.

X is preferably —C(O)—.

Y is preferably —O—.

Z includes preferably (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7),(Z-8), and (Z-9). It is more preferably (Z-3).

M includes preferably C₁₋₃ alkylene optionally substituted with 1 to 3the same or different substituents selected from the group consisting offluorine atom, C₂₋₄ alkynyl, C₁₋₃ alkoxy, —NR^(36A)R^(37A), and cyano.It includes more preferably C₁₋₃ alkylene. It includes even morepreferably methylene.

Q includes preferably C₃₋₆ cycloalkyl optionally-substituted with 1 to 3the same or different substituents selected from the group consisting offluorine atom, C₁₋₃ alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), andcyano; 3- to 6-membered saturated heterocyclyl optionally-substitutedwith 1 to 3 the same or different substituents selected from the groupconsisting of fluorine atom, C₁₋₃ alkyl, —NR^(36A)SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano; phenyl optionally-substituted with 1 to3 the same or different substituents selected from the group consistingof fluorine atom, C₁₋₂ alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A),and cyano; and 5- to 6-membered heteroaryl optionally-substituted with 1to 3 the same or different substituents selected from the groupconsisting of fluorine atom, C₁₋₃ alkyl, —NR^(36A)SO₂R^(35A),—SO₂NR^(36A)R^(37A), and cyano. It includes more preferably C₃₋₆cycloalkyl optionally-substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano. It includeseven more preferably C₃₋₆ cycloalkyl optionally-substituted with 1 to 3the same or different substituents selected from the group consisting offluorine atom and C₁₋₃ alkyl. C₃₋₆ cycloalkyl is especially preferable.

The symbols a and c include preferably 1.

In an embodiment, both of b and d include 1. In another embodiment, bothof b and d include 2.

U is preferably nitrogen atom.

R¹ includes preferably hydrogen atom or -M-Q.

R² includes preferably hydrogen atom or -M-Q.

R³ includes preferably hydrogen atom or fluorine atom.

R⁴ includes preferably hydrogen atom or fluorine atom.

In another embodiment, R¹ and R² are combined together to form═CR^(12A)R^(13A). It is more preferably ═CH₂.

In another embodiment, R³ and R⁴ are combined together to form═CR^(12A)R^(13A). It is more preferably ═CH₂.

In another embodiment of R¹, R², R³, and R⁴, R¹ is hydrogen atom, R² is-M-Q, R³ is hydrogen atom, and R⁴ is hydrogen atom or fluorine atom.

In another embodiment of R¹, R², R³, and R⁴, R¹ is -M-Q, R² is hydrogenatom, R³ is hydrogen atom or fluorine atom, and R⁴ is hydrogen atom.

In another embodiment of R¹, R², R³, and R⁴, R¹ and R² are both hydrogenatom, and R³ and R⁴ are combined together to form ═CH₂.

In another embodiment of R¹, R², R³, and R⁴, R³ and R⁴ are both hydrogenatom, and R¹ and R² are combined together to form ═CH₂.

In another embodiment of R¹, R², R³, and R⁴, R¹ and R² are both hydrogenatom, R³ is hydrogen atom, and R⁴ is fluorine atom.

In another embodiment of R¹, R², R³, and R⁴, R¹ and R² are both hydrogenatom, R³ is fluorine atom, and R⁴ is hydrogen atom.

R^(5A) and R^(5B) are preferably hydrogen atom.

R^(6A), R^(6B), and R^(6D) are preferably hydrogen atom.

R^(6C) is preferably fluorine atom.

R⁷ includes preferably hydrogen atom, C₁₋₆ alkyl, or C₂₋₆ alkenyl,wherein the alkyl or the alkenyl may be substituted with one phenyl.

R⁸, R¹⁴, R¹⁸, R²⁵, R³¹, R^(35A), and R^(35B) are preferably C₁₋₃ alkyl.

R⁹, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²³, R²⁴, R²⁶, R²⁷, R²⁸,R²⁹, R³⁰, R³², R³³, R³⁴, R^(36A), R^(36B), R^(37A), and R^(37B) includepreferably hydrogen atom or C₁₋₃ alkyl.

R^(12A) and R^(13A) include preferably C₃₋₆ cycloalkyloptionally-substituted with 1 to 3 the same or different substituentsselected from the group consisting of hydrogen atom or fluorine atom,C₁₋₃ alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano. It ismore preferably hydrogen atom.

R^(12B) and R^(13B) include preferably C₁₋₃ alkyl.

R²² is preferably —CF₃ or cyano.

In an embodiment, the present compound of formula (1) includes thefollowing (A).

(A)

A Compound or pharmaceutically acceptable salt thereof, wherein

formula (1) is formula (1a);

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₃ alkylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, or C₃₋₆cycloalkyl which may be substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areeach attached to form 3- to 6-membered nitrogen-containing saturatedheterocycle;

a and c are 1; and

both b and d are either 1 or 2.

An embodiment of the present compound of formula (1) includes thefollowing (B):

(B)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₃ alkylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, or C₃₋₆cycloalkyl which may be substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areeach attached to form 3- to 6-membered nitrogen-containing saturatedheterocycle;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom:

R^(6C) is fluorine atom;

U is nitrogen atom;

Y is —O—; and

Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), or (Z-9).

An embodiment of the present compound of formula (1) includes thefollowing (C):

(C)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to formeach independently ═O or ═CR^(12A)R^(13A);

M is, each independently if there are plural, C₁₋₃ alkylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl which maybe substituted with 1 to 3 the same or different substituents selectedfrom the group consisting of fluorine atom, C₁₋₃ alkyl,—NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(12A) and R^(13A) are each independently hydrogen atom, or C₃₋₆cycloalkyl which may be substituted with 1 to 3 the same or differentsubstituents selected from the group consisting of fluorine atom, C₁₋₃alkyl, —NR^(36A)SO₂R^(35A), —SO₂NR^(36A)R^(37A), and cyano;

R^(35A) is, each independently if there are plural, C₁₋₆ alkyl;

R^(36A) and R^(37A) are each independently hydrogen atom or C₁₋₆ alkyl,and if there are plural R^(36A) or R^(37A), each R^(36A) or R^(37A) maybe the same or different, or when R^(36A) and R^(37A) are both C₁₋₆alkyl, they may be combined with the nitrogen atom to which they areattached to form 3- to 6-membered nitrogen-containing saturatedheterocycle;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is CR²²;

R²² is —CF₃ or cyano;

Y is —O—; and

Z is (Z-3).

An embodiment of the present compound of formula (1) includes thefollowing (D):

(D)

A compound or pharmaceutically acceptable salt thereof, wherein

formula (1) is formula (Ia);

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to form═CH₂;

M is, each independently if there are plural, methylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl;

a and c are 1; and

both b and d is either 1 or 2.

An embodiment of the present compound of formula (1) includes thefollowing (E):

(E)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to form═CH₂;

M is, each independently if there are plural, methylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is nitrogen atom;

Y is —O—; and

Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), or (Z-9).

An embodiment of the present compound of formula (1) includes thefollowing (F):

(F)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom, fluorine atom,or -M-Q; or R¹ and R² and/or R³ and R⁴ may be combined together to form═CH₂;

M is, each independently if there are plural, methylene;

Q is, each independently, if there are plural, C₃₋₆ cycloalkyl;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is CR²²;

R²² is —CF₃ or cyano;

Y is —O—; and

Z is (Z-3).

An embodiment of the present compound of formula (1) includes thefollowing (G):

(G)

A compound or pharmaceutically acceptable salt thereof, wherein

formula (1) is formula (1a);

p is 1 or 2;

R¹ and R² are hydrogen atom;

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

a and c are 1; and

both b and d are either 1 or 2;

provided that both R³ and R⁴ are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (H):

(H)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹ and R² are hydrogen atom;

R³ and R⁴ are each independently hydrogen atom or

fluorine atom;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is nitrogen atom;

Y is —O—; and

Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), or (Z-9);

provided that both R³ and R⁴ are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (I):

(I)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹ and R² are hydrogen atom;

R¹ and R⁴ are each independently hydrogen atom or fluorine atom;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is CR²²;

R²² is —CF₃ or cyano;

Y is —O—; and

Z is (Z-3),

provided that both R³ and R⁴ are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (J):

(J)

A compound or pharmaceutically acceptable salt thereof, wherein

formula (1) is formula (1a);

p is 1 or 2;

R¹ and R² are each independently hydrogen atom or -M-Q;

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

M is, each independently if there are plural, methylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl;

a and c are 1; and

both b and d are either 1 or 2;

provided that both R¹ and R² are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (K):

(K)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹ and R² are each independently hydrogen atom or -M-Q;

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

M is, each independently if there are plural, methylene;

Q is, each independently, if there are plural, C₃₋₆ cycloalkyl;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is nitrogen atom;

Y is —O—; and

Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), or (Z-9),

provided that both R¹ and R² are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (L):

(L)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹ and R² are each independently hydrogen atom or -M-Q;

R³ and R⁴ are each independently hydrogen atom or fluorine atom;

M is, each independently if there are plural, methylene;

Q is, each independently if there are plural, C₃₋₆ cycloalkyl,

X is —C(O)—;

a and c are 1;

both b and c are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is CR²²;

R²² is —CF₃ or cyano;

Y is —O—; and

Z is (Z-3);

provided that both R¹ and R² are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (M):

(M)

A compound or pharmaceutically acceptable salt thereof, wherein

formula (1) is formula (1a);

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom; or R¹ and R²and/or R³ and R⁴ may be combined together to form ═CH₂;

a and c are 1; and

both b and d are either 1 or 2;

provided that all of R¹, R², R³, and R⁴ are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (N):

(N)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom; or R¹ and R²and/or R³ and R⁴ may be combined together to form ═CH₂;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is nitrogen atom;

Y is —O—; and

Z is (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), or (Z-9);

provided that all of R¹, R², R³, and R⁴ are not hydrogen atom.

An embodiment of the present compound of formula (1) includes thefollowing (O):

(O)

A compound or pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

R¹, R², R³, and R⁴ are each independently hydrogen atom; or R¹ and R²and/or R³ and R⁴ may be combined together to form ═CH₂;

X is —C(O)—;

a and c are 1;

both b and d are either 1 or 2;

R^(5A), R^(5B), R^(6A), R^(6B), and R^(6D) are hydrogen atom;

R^(6C) is fluorine atom;

U is CR²²;

R²² is —CF₂ or cyano;

Y is —O—; and

Z is (Z-3),

provided that all of R¹, R², R³, and R⁴ are not hydrogen atom.

Hereinafter, the processes to prepare the compound of the presentinvention of formula (1) are exemplified along with examples, but theprocesses to prepare the compound of the present invention should not belimited to the examples. Compounds used in the following process mayexist as their salts unless they affect reactions.

The compound of the present invention can be prepared from knowncompounds as starting materials, for example, by the following methodsA, B, C, D, E, F, G, H, I, J, K, L, M, N, and O, or similar methodsthereto, or optionally in combination with synthetic methods well-knownto a person skilled in the art.

Preparation Process A

The compound of the present invention of formula (1) can be prepared,for example, by the following process:

wherein a, b, c, d, p, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), U, X, Y, and Z are as defined in Item 1; LG¹ is aleaving group; and P¹ is an amino-protecting group, wherein LG¹includes, for example, halogen atom, methanesulfonyloxy,p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, phenoxy,trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy,and the like; P¹ includes, for example, amino-protecting groupsdescribed in T. W. Greene, and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1999), and the like; andthe stereochemistry of the carbon with * is not inverted duringreactions.

(Step 1)

Compound (a3) can be prepared by reacting compound (a1) obtained in thefollowing process with compound (a2) obtained in the following procedurein the presence or absence of an appropriate base in an appropriatesolvent.

Compound (a1) used herein can be obtained by the following preparationprocess B (as compound (a1)), by the following preparation process D(compound (D1)), or by the following preparation process E (compound(E1)). Compound (a2) used herein can be obtained by the followingpreparation process F (as compound (F1)), or by the followingpreparation process G (compound (G1)).

The base used herein includes, for example, organic bases such astriethylamine, diisopropylethylamine, tributylamine,1.5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM), andinorganic bases such as sodium bicarbonate, potassium bicarbonate,sodium carbonate, potassium carbonate, sodium hydroxide, and potassiumhydroxide. The base includes preferably triethylamine,diisopropylethylamine, potassium carbonate, sodium hydroxide, and thelike.

The solvent used herein includes, for example, alcohol solvents such asmethanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol;ether solvents such as diethyl ether, diisopropyl ether,tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatichydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole,and xylene; ester solvents such as ethyl acetate, and methyl acetate;aprotic solvents such as acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; and mixturesthereof, but not specifically limited thereto unless it reacts under thereaction condition in the present processes. The solvent includespreferably 2-propanol, tetrahydrofuran, toluene, acetonitrile,N,N-dimethylformamide, and the like.

The reaction temperature is generally −80° C. to reflux temperature,preferably 25° C. to 90° C.

The reaction time is generally 30 minutes to 48 hours, preferably 6 to12 hours.

Alternatively, compound (a1) may be coupled with compound (a2) in thepresence of an appropriate metal catalyst in an appropriate solvent. Thereaction condition includes, for example, Ulmann-type condition (forexample, heating under reflux with a metal catalyst such as copper(II)acetate in an aprotic solvent such as DMF), Buchwald-type condition (forexample, heating under reflux with alkali metal carbonate such as cesiumcarbonate; BINAP; a palladium catalyst such as Pd₂(dba)₃ and Pd(OAc)₂;and a ligand such as dppf and Xantphos, in an inert solvent under thereaction conditions such as toluene).

The solvent used herein includes, for example, alcohol solvents such asmethanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol;ether solvents such as diethyl ether, diisopropyl ether,tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatichydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole,and xylene; ester solvents such as ethyl acetate and methyl acetate;aprotic solvents such as acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; water; andmixtures thereof, but should not specifically limited thereto unless itreacts under the reaction condition in the present processes. Thesolvent includes preferably tetrahydrofuran, toluene, acetonitrile,N,N-dimethylformamide, and the like.

The reaction temperature is generally −80° C. to reflux temperature,preferably 25° C. to 90° C.

The reaction time is generally 30 minutes to 48 hours, preferably 6 to12 hours.

(Step 2)

Compound (1) can be prepared by removing protecting group P¹ fromcompound (a3). The present step can be carried out according to a knownmethod described, for example, in T. W. Greene, P. G. M. Wuts,“Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc.,(1999), or a similar method.

Preparation Process B

The compound of formula (a1) can be prepared, for example, by thefollowing process:

wherein R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), R^(6D), U, Y, and Z areas defined in Item 1, LG¹ is as defined in preparation process A, LG² isa leaving group, and P² is a hydroxy-protecting group, wherein LG²includes, for example, halogen atom, methanesulfonyloxy,p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, phenoxy,trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy,and the like; and P² includes, for example, hydroxy-protecting groupsdescribed in T. W. Greene, and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1999), and the like.

Compound (b1) and compound (b2) are commercially available.

(Step 1)

Compound (b3) can be prepared from compound (b1) and compound (b2)according to the process of step 1 in preparation process A or a similarmethod.

(Step 2)

Compound (b4) can be prepared by removing protecting group P² fromcompound (b3). The present step can be carried out according to a knownmethod described, for example, in T. W. Greene, and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc.,(1999), or a similar method.

(Step 3)

Compound (a1) can be prepared from compound (b4) according to a knownmethod described in J. Med. Chem., 53(16): 6129-6152 (2010), J. Med.Chem., 59(17): 7936-7949 (2016), J. Org. Chem., 76(10): 4149-4153(2011), European Journal of Medicinal Chemistry, 44(10): 4179-4191(2009), or a similar method.

Preparation Process C

The compound of formula (b3) can be prepared, for example, by thefollowing process:

wherein R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), R^(6D), U, Y, and Z areas defined in Item 1; and LG² and P² are as defined in preparationprocess B.

Compound (c1) is commercially available, and compound (c2) can beprepared according to a known method described in WO 2017/214367 or asimilar method, or can be obtained as a marketed product.

(Step 1)

Compound (b3) can be prepared from compound (c1) and compound (c2)according to the method described in step 1 of preparation process A ora similar method.

Preparation Process D

In the compound of formula (a1), the compound of formula (D1) can beprepared, for example, by the following method:

wherein R^(6A), R^(6B), R^(6C), R^(6D), U, and Z are as defined in Item1; and LG¹ is as defined in preparation process A.

Compound (d1) can be prepared by a known method described in WO2017/214367 or a similar method, or can be obtained as a marketedproduct.

(Step 1)

Compound (d2) can be prepared by a known method described in Bioorganic& Medicinal Chemistry Letters, 22(24): 7456-7460 (2012), Bioorganic &Medicinal Chemistry Letters, 12(8): 1185-1187 (2002), Bioorganic &Medicinal Chemistry, 23(1): 132-140 (2015), Bioorganic & MedicinalChemistry, 19(1): 211-220 (2011), or a similar method.

(Step 2)

Compound (d3) can be prepared from compound (d2) by a known methoddescribed in European Journal of Medicinal Chemistry, 23(1): 53-62(1988), Tetrahedron, 62(23): 5469-5473 (2006), WO 2008/092049, WO2015/175707, or a similar method.

(Step 3)

Compound (d4) can be prepared from compound (d3) by a known methoddescribed in J. Med. Chem., 23(9): 1026-1031 (1980), WO 2003/087067, WO2000/061562, or a similar method.

(Step 4)

Compound (D1) can be prepared from compound (d4) by a known methoddescribed in European Journal of Medicinal Chemistry, 44(10): 4179-4191(2009), J. Org. Chem., 76(10): 4149-4153 (2011), J. Med. Chem., 53(16):6129-6152 (2010), J. Med. Chem., 59(17): 7936-7949 (2016), or a similarmethod.

Preparation Process E

In the compound of formula (a1), the compound of formula (E1) can beprepared, for example, by the following method:

wherein R^(6A), R^(6B), R^(6C), R^(6D), and Z are as defined in Items 1;and LG¹ is as defined in preparation process A.

Compound (d1) can be prepared by a known method described in WO2017/214367 or a similar method, or can be obtained as a marketedproduct.

(Step 1)

Compound (e1) can be prepared from compound (d1) according to the methoddescribed in step 1 of preparation process C, or a similar method.

(Step 2)

Compound (e2) can be prepared from compound (e1) by a known methoddescribed in J. Org. Chem., 82(17): 8933-8942 (2017), Tetrahedron, 68(29): 5845-5851 (2012), J. Am. Chem. Soc., 139 (16): 5998-6007 (2017),Angewandte Chemie, International Edition, 45(46): 7781-7786 (2006), or asimilar method.

(Step 3)

Compound (E1) can be prepared from compound (e2) by a known methoddescribed in WO 2017/214367, WO 2009/137733 or a similar method.

Preparation Process F

In the compound of formula (a2), the compound of formula (F1) can beprepared, for example, by the following method:

wherein a, b, c, d, p, R¹, R², R³, and R⁴ are as defined in Item 1; P¹is as defined in preparation process A; LG³ is a leaving group; and P³is an amino-protecting group, wherein LG³ includes, for example, halogenatom, hydroxy, and the like; P³ includes, for example, amino-protectinggroups described in T. W. Greene, and P. G. M. Wuts, “Protective Groupsin Organic Synthesis”, John Wiley & Sons, Inc., (1999), and the like;and the stereochemistry of the carbon with * is not inverted duringreactions.

Compound (f1) is commercially available.

Compound (f2) can be prepared by a known method described inJP-A-2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988),Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2:1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016),Comprehensive Organic Transformation 2^(nd) Edition (Larock R. C., JohnWiley & Sons, Inc., (1989)) or a similar method, or can be obtained as amarketed product.

(Step 1)

Compound (f3) can be prepared by reacting compound (f1) with compound(f2) such as carboxylic acid compound or acid chloride compound in thepresence of an appropriate condensing agent and/or an appropriate basein an appropriate solvent.

The base used herein includes amines such as triethylamine,diisopropylethylamine, and pyridine; carbonates of alkali metal such aspotassium carbonate, sodium carbonate, and sodium bicarbonate.

The condensing agent used herein is optionally selected from condensingagents commonly-used in organic synthetic chemistry, and includespreferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and the like.

The solvent used herein includes, for example, ether solvents such asdiethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentylether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene,toluene, chlorobenzene, anisole, and xylene; ester solvents such asethyl acetate, and methyl acetate; aprotic solvents such asacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, anddimethylsulfoxide; halogenated hydrocarbon solvents such asdichloromethane (methylene chloride), chloroform, and1,2-dichloroethane; and mixtures thereof, but should not be specificallylimited thereto unless it reacts under the reaction condition of thepresent step. The solvent includes preferably tetrahydrofuran, toluene,acetonitrile, N,N-dimethylformamide, dichloromethane, and the like.

The reaction time is generally 5 minutes to 72 hours, preferably 30minutes to 24 hours. The reaction temperature is generally −78° C. to200° C., preferably −78° C. to 80° C.

(Step 2)

Compound (F1) can be prepared by removing protecting group P³ fromcompound (f3). The present step can be carried out, for example,according to a known method described in T. W. Greene, and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc.,(1999), or a similar method.

Preparation Process G

In the compound of formula (a2), the compound of formula (G1) can beprepared, for example, by the following process:

wherein a, b, c, d, p, R¹, R², R³, and R⁴ are as defined in Item 1; P¹is as defined in preparation process A; P³ is as defined in preparationprocess F; and the stereochemistry of the carbon with * is not invertedduring reactions.

Compound (f1) is commercially available.

Compound (g1) can be obtained by a known method described inJP-A-2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988),Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2:1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016), R. C.Larock, “Comprehensive Organic Transformation 2^(nd) Edition”, JohnWiley & Sons, Inc., (1989) or a similar method, or can be obtained as amarketed product.

(Step 1)

Compound (g2) can be prepared from compound (f1) and compound (g1) by aknown method described in J. Am. Chem. Soc., 93(12): 2897-2904 (1971),J. Org. Chem., 37(10): 1673-1674 (1972), J. Org. Chem., 61(11):3849-3862 (1996), Tetrahedron, 60: 7899-7906 (2004), or a similarmethod.

(Step 2)

Compound (G1) can be prepared by removing protecting group P³ fromcompound (g2). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process H

The compound of formula (H1) can be prepared, for example, by thefollowing process:

wherein a, b, c, d, p, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), U, Y, and Z are as defined in Item 1; LG¹ is as definedin preparation process A; LG¹ is as defined in preparation process F; P¹is as defined in preparation process A; and P⁴ is an amino-protectinggroup, wherein P⁴ includes, for example, amino-protecting groupsdescribed in T. W. Greene, and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1999), and the like; andthe stereochemistry of the carbon with * is not inverted duringreactions.

Compound (h1) is commercially available.

(Step 1)

Compound (h2) can be prepared from compound (a1) and compound (h1) bythe method described in step 1 of preparation process A or a similarmethod.

(Step 2)

Compound (h3) can be prepared by removing protecting group P⁴ fromcompound (h2). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

(Step 3)

Compound (h4) can be prepared from compound (h3) and compound (f2) bythe method described in step 1 of preparation process F or a similarmethod.

(Step 4)

Compound (H1) can be prepared by removing P¹ from compound (h4). Thepresent step can be carried out, for example, by a known methoddescribed in T. W. Greene, and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1999), or a similarmethod.

Preparation Process I

The compound of the present invention of formula (I1) can be prepared,for example, by the following method:

wherein a, b, c, d, p, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), U, Y, and Z are as defined in Item 1; P¹ is as definedin preparation process A; and the stereochemistry of the carbon with *is not inverted during reactions.

(Step 1)

Compound (i1) can be prepared from compound (h3) and compound (g1) by aknown method described in step 1 of preparation process G or a similarmethod.

(Step 2)

Compound (I1) can be prepared by removing protecting group P¹ fromcompound (i1). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process J

In the compound of formula (f2), the compound of formula (J1) can beprepared, for example, by the following method:

wherein p and Q are as defined in Item 1; P¹ is as defined inpreparation process A; P⁵ is a protecting group of carboxylic acid,wherein P⁵ includes, for example, carboxylic acid-protecting groupsdescribed in T. W. Greene, and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1999), and the like; andthe stereochemistry of the carbon with * is not inverted duringreactions.

Compound (j1) can be prepared by a known method described inJP-A-2007-510619, J. Chem. Soc., Chem. Commun., 1599-1601 (1988),Tetrahedron Letters, 43: 5957-5960 (2002), Tetrahedron Asymmetry, 2:1263-1282 (1991), Tetrahedron Asymmetry, 27: 1062-1068 (2016), R. C.Larock, “Comprehensive Organic Transformation 2^(nd) Edition”, JohnWiley & Sons, Inc., (1989) or a similar method, or can be obtained as amarketed product.

(Step 1)

Compound (j2) can be prepared from compound (j1) by a known methoddescribed in Tetrahedron Letters, 27: 2567-2570 (1986), Synthesis, 12:1930-1935 (2011), Bioorganic & Medicinal Chemistry Letters, 23:4493-4500 (2013), European Journal of Organic Chemistry, 10: 2485-2490(1999), or a similar method.

(Step 2)

Compound (j3) can be prepared from compound (j2) by a known methoddescribed in Synthetic Communications, 28: 1743-1753 (1998), ChemistryLetters, 6: 875-878 (1983), Journal of Organic Chemistry, 28: 6-16(1963) or a similar method.

(Step 3)

Compound (j4) can be prepared from compound (j3) by a known methoddescribed in Tetrahedron Letters, 23: 477-480 (1982), Synlett, 443-444(1995), Synlett, 96-98 (1999), Tetrahedron, 56: 2779-2788 (2000) or asimilar method.

(Step 4)

Compound (J1) can be prepared by removing protecting group P⁵ fromcompound (j4). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process K

In the compound of formula (f2), the compound of formula (K1) can beprepared, for example, by the following method:

wherein p and Q are as defined in Item 1; P¹ is as defined inpreparation process A; P⁵ is as defined in preparation process J; andthe stereochemistry of the carbon with * is not inverted duringreactions.

Compound (k1) is commercially available.

(Step 1)

Compound (j3) can be prepared from compound (j1) and compound (k1) by aknown method described in Journal of the American Chemical Society, 126:14206-14216 (2004), Synthetic Communications, 20: 839-847 (1990),Synthesis, 23: 3821-3826 (2011), Advanced Synthesis & Catalysis, 352:153-162 (2010) or a similar method.

(Step 2)

Compound (K1) can be prepared by removing protecting group P⁵ fromcompound (j3). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process L

In the compound of formula (f2), the compound of formula (L1) can beprepared, for example, by the following method:

wherein p, M, and Q are as defined in Item 1; LG⁴ is a leaving group; P¹is as defined in preparation process A; P⁵ is as defined in preparationprocess J, wherein LG⁴ includes, for example, halogen atom,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,phenoxy, trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy,nitrophenoxy, and the like; and the stereochemistry of the carbon with *is not inverted during reactions.

Compound (l1) is commercially available.

(Step 1)

Compound (l2) can be prepared from compound (j1) and compound (l1) by aknown method described in Journal of the American Chemical Society, 132:1236-1237 (2010), Journal of Medicinal Chemistry, 49: 4409-4424 (2006),Advanced Synthesis & Catalysis, 357: 2803-2808 (2015), TetrahedronLetters, 47 (19): 3233-3237 (2006), Angewandte Chemie, InternationalEdition, 44(34): 5516-5519 (2005), or a similar method.

(Step 2)

Compound (L1) can be prepared by removing protecting group P⁵ fromcompound (12). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process M

The compound of the present invention of formula (1) can be prepared,for example, by the following method:

wherein a, b, c, d, p, R¹, R², R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B),R^(6C), R^(6D), U, X, Y, and Z are as defined in Item 1; LG¹ is asdefined in preparation process A; and the stereochemistry of the carbonwith * is not inverted during reactions.

Compound (1) can be prepared from compound (a1) and compound (m1) whichis prepared by the following preparation process, by a known methoddescribed in step 1 of preparation process A or a similar method.

Compound (m1) used herein can be obtained by the following preparationprocess N (as compound (N1)), or by the following preparation process O(compound (O1)).

Preparation Process N

In the compound of formula (m1), the compound of formula (N1) can beprepared, for example, by the following method:

wherein a, b, c, d, p, R¹, R², R³, and R⁴ are as defined in Item 1; LG³is as defined in preparation process F; P¹ is as defined in preparationprocess A; and the stereochemistry of the carbon with * is not invertedduring reactions.

Compound (n1) is commercially available.

(Step 1)

Compound (n2) can be prepared from compound (n1) and compound (f2) bythe method described in step 1 of preparation process F or a similarmethod.

(Step 2)

Compound (N1) can be prepared by removing protecting group P¹ fromcompound (n2). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

Preparation Process O

In the compound of formula (m1), the compound of formula (O1) can beprepared, for example, by the following method:

wherein a, b, c, d, p, R¹, R², R³, and R⁴ are as defined in Item 1; P¹is as defined in preparation process A; and the stereochemistry of thecarbon with * is not inverted during reactions.

(Step 1)

Compound (o1) can be prepared from compound (n1) and compound (g1) by aknown method described in step 1 of preparation process G or a similarmethod.

(Step 2)

Compound (O1) can be prepared by removing protecting group P¹ fromcompound (o1). The present step can be carried out, for example, by aknown method described in T. W. Greene, and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., (1999), or asimilar method.

In the above preparation processes, starting materials or intermediateswhich are not described for preparation processes can be obtained asmarketed products, or can be prepared from marketed products by a methodwell-known to those skilled in the art.

In each reaction described above, protecting groups can be used asnecessary, even if the use of protecting groups is not explicitlystated. For example, when any one or more functional groups other thanreaction sites are converted to undesired forms under the reactioncondition, or the process described above cannot be carried out properlywithout protecting groups, protecting groups can be used to protectgroups other than reaction sites as necessary, and can be deprotectedafter the reaction is completed or a series of reactions have beencarried out to obtain the desired compound.

As such protecting groups, for example, the groups described in T. W.Greene, and P. G. M. Wuts, “Protective Groups in Organic Synthesis”,John Wiley & Sons, Inc., (1999), and the like may be used. Examples ofamino-protecting groups include, for example, benzyloxycarbonyl,tert-butoxycarbonyl, acetyl, benzyl, and the like. Examples ofhydroxy-protecting groups include, for example, trialkylsilyl such astrimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, and thelike.

The introduction and elimination of protecting groups can be carried outby a method commonly-used in synthetic organic chemistry (for example,see “Protective Groups in Organic Synthesis” described above), or asimilar method.

In the present specification, protecting groups, condensing agents andthe like may be described in an abbreviated form according to IUPAC-IUB(Biochemical nomenclature committee) commonly-used herein. It should beunderstood that the names of compounds used in the present specificationdo not necessarily follow the IUPAC nomenclature.

The intermediates or the desired compounds which are described in theabove preparation processes can be transformed to other compounds whichfall within the present invention by optionally converting theirfunctional groups to other groups (for example, the conversion fromamino, hydroxy, carbonyl, halogen atom, and the like, while protectingor deprotecting other functional groups as necessary). The conversion offunctional groups can be carried out by a general method which arecommonly used (see, for example, R. C. Larock, “Comprehensive OrganicTransformations”, John Wiley & Sons Inc. (1999)).

The intermediates and the desired compounds described above can beisolated and purified by a purification method commonly-used in organicsynthetic chemistry (for example, neutralization, filtration,extraction, washing, drying, enrichment, recrystallization, variouschromatography, and the like). In addition, intermediates may be used innext reaction without further purification.

The “pharmaceutically acceptable salt” includes acid addition salts andbase addition salts. For example, the acid addition salt includesinorganic acid salts such as hydrochloride, hydrobromide, sulfate,hydroiodide, nitrate, and phosphate; or organic acid salts such ascitrate, oxalate, phthalate, fumarate, maleate, succinate, malate,acetate, formate, propionate, benzoate, trifluoroacetate,methanesulfonate, benzenesulfonate, p-toluenesulfonate, andcamphorsulfonate. The base addition salt includes inorganic base saltssuch as sodium salts, potassium salts, calcium salts, magnesium salts,barium salts, and aluminum salts; and organic base salts such astrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. The“pharmaceutically acceptable salt” also includes amino acid salts ofbasic or acidic amino acids such as arginine, lysine, ornithine,aspartate, and glutamate.

The suitable salts of starting materials and intermediates andacceptable salts of drug substances are conventional non-toxic salts.The suitable salt includes, for example, acid addition salts such asorganic acid salts (including acetate, trifluoroacetate, maleate,fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate,formate, and p-toluenesulfonate) and inorganic acid salts (includinghydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, andphosphate); salts with amino acids (including arginine, aspartate, andglutamate); alkali metal salts (including sodium salts, and potassiumsalts); alkaline earth metal salts (including calcium salts, andmagnesium salts); ammonium salts; organic base salts (includingtrimethylamine salts, triethylamine salts, pyridine salts, picolinate,dicyclohexylamine salts, and N,N′-dienzylethylenediamine salts); andother salts which a person skilled in the art can optionally select.

In the present invention, the “hydrogen atom” includes ¹H and ²H (D),and the compound of formula (1) encompasses deuterated compounds inwhich any one or more ¹H in the compound of formula (1) are replacedwith ²H (D).

The present invention encompasses compounds of formula (1) orpharmaceutically acceptable salts thereof. The compound of the presentinvention may exist in a form of hydrate and/or solvate of varioussolvents, including ethanolate, and these hydrate and/or solvate areincluded in the compound of the present invention.

The compound of the present invention encompasses optical isomers basedon an optically active center, atropisomers based on axial or planarchirality caused by restriction of intramolecular rotation, and allother isomers which can exist as stereoisomers, tautomers, and geometricisomers, and crystalline forms in various states, and mixtures thereof.

Especially, each optical isomer and atropisomer can be obtained as aracemate, or as an optically active substance when an optically activestarting material or intermediate is used. Racemates of correspondingstarting materials, intermediates, or final products can also bephysically or chemically resolved into optical enantiomers by a knownisolating method such as a method with an optically active column and afractional crystallization method, at an appropriate step in the abovepreparation processes, if necessary. These methods for resolvingenantiomers include a diastereomer method in which, for example, aracemate is reacted with an optically active resolving agent tosynthesize 2 kinds of diastereomers, which are resolved by fractionalcrystallization or a similar method through different physicalproperties.

If the compound of the present invention should be obtained as apharmaceutically acceptable salt thereof, when the compound of formula(1) is obtained as a pharmaceutically acceptable salt, it may bepurified without further reaction, and when it is obtained in a freeform, it may be solved or suspended in an appropriate organic solventand an acid or base may be added therein to form a salt by a commonmethod.

In the present invention, the “agent used in combination” is anantitumor medicament which can be used in combination with the compoundof the present invention or can be combined with the compound of thepresent invention in a pharmaceutical composition. The “combinationdrug” includes, for example, an antitumor alkylating agent, an antitumorantimetabolite, an antitumor antibiotic, a plant-derived antitumormedicament, an antitumor platinum complex compound, an antitumorcamptothecin derivative, an antitumor tyrosine kinase inhibitor, anantitumor serine/threonine kinase inhibitor, an antitumor phospholipidkinase inhibitor, an antitumor monoclonal antibody, interferon, anbiological response modifier, a hormone preparation, an immunecheckpoint inhibitor, an epigenetics-associated molecular inhibitor, aprotein post-translational modification inhibitor, and other antitumormedicaments. Examples of the “combination drug” include, for example,azacytidine, vorinostat, decitabine, romidepsin, idarubicin,daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone,thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine,temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine,all-trans retinoic acid, tamibarotene, cisplatin, carboplatin,oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate,paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur,fluorouracil, everolimus, temsirolimus, gefitinib, erlotinib, imatinib,crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib,sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib,ibrutinib, ceritinib, alectinib, tofacitinib, baricitinib, ruxolitinib,olaparib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib,bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab,panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab,ofatumumab, ipilimumab, ramucirumab, brentuximab vedotin, Gemtuzumabozogamicin, inotuzumab ozogamicin, and the like.

The administration route of the compound of the present invention may beoral, parenteral, intrarectal, or ophthalmic administration, and thedaily dose depends on the type of compounds, administration methods, thecondition or age of patients, and the like. For example, in the case oforal administration, about 0.01 to 1000 mg, more preferably about 0.1 to500 mg per kg body weight of a human or mammal can be usuallyadministrated in one to several portions. In the case of parenteraladministration such as intravenous injection, for example, about 0.01 mgto 300 mg, more preferably about 1 mg to 100 mg per kg body weight of ahuman or mammal can be usually administrated.

The compound of the present invention can be orally or parenterallyadministrated directly or as a suitable drug formulation. The dosageform includes, for example, a tablet, a capsule, a powder, a granule, aliquid, a suspension, an injection, a patch, a poultice, and the like,but it is not limited to them. The drug formulation is prepared by acommon method using pharmaceutically acceptable additives.

As the additive, an excipient, a disintegrant, a binder, a fluidizer, alubricant, a coating agent, a solubilizer, a solubilizing adjuvant, athickener, a dispersant, a stabilizing agent, a sweetening agent, aflavor, and the like may be used, depending on purpose. The additiveused herein includes, for example, lactose, mannitol, crystallinecellulose, low-substituted hydroxypropylcellulose, corn starch,partially-pregelatinized starch, carmellose calcium, croscarmellosesodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, magnesium stearate, sodium stearyl fumarate, polyethyleneglycol, propylene glycol, titanium oxide, talc, and the like.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Reference examples, Examples, and Tests; however, thetechnical scope of the present invention should not be limited thereto.

In the present specification, the abbreviations shown below may be used.

THF: tetrahydrofuranTFA: trifluoroacetic acid

DMF: N,N-dimethylformamide

DMSO: dimethylsulfoxideMeCN: acetonitrileMe: methylEt: ethylPh: phenylBn: benzylBoc: tert-butoxycarbonyln-: normal-tert-: tertiary-p-: para-BINAP: 2,2′-bis(diphenyiphosphino)-1,1′-binaphthylPd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)Ac: acetyldppf: 1,1′-bis(diphenylphosphino)ferroceneXantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneDess-Martin reagent: Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)Petasis reagent: bis(cyclopentadienyl)dimethyltitaniumBredereck reagent: tert-butoxy-bis(dimethylamino)methaneHATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate

WSCI.HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazole

NMR (Nuclear Magnetic Resonance) data used for identification ofcompounds were obtained with a JNM-ECS400 type nuclear magneticresonance instrument (400 MHz) from JEOL Ltd.

The symbols used in NMR are defined as follows, s: singlet, d: doublet,dd: doublet of doublet, t: triplet, td: triplet of doublet, q: quartet,m: multiplet, br: broad, brs: broad singlet, brm: broad multiplet, andJ: coupling constant.

Analytical conditions of LC/MS (Liquid Chromatography-Mass Spectrometry)used for identification of compounds are shown below. In observed massspectrometry values, monoisotopic mass (exact mass consisting of onlymain isotope) is shown in [M+H]⁺, [M−H]⁻, or [M+2H]²⁺, etc., andretention time is shown as Rt (minutes).

The analytical conditions of LC/MS:

Analytical condition ADetection apparatus: ACQUITY™ SQ detector (Waters Corporation)HPLC: ACQUITY™ UPLC systemColumn: Waters ACQUITY™ UPLC BEH C18 (1.7 μm, 2.1 mm×30 mm)Solvent: A: 0.06% formic acid/H₂O, B: 0.06% formic acid/MeCNGradient condition: 0.0 to 1.3 minutes Linear gradient of B 2% to B 96%Flow rate: 0.8 mL/min

UV: 220 nm and 254 nm

Column temperature: 40° C.

Analytical Condition B

Detection apparatus: LCMS-2020 (Shimadzu Corporation)

HPLC: Nexera X2

Column: Phenomenex Kinetex™ 1.7 μm C18 (50 mm×2.1 mm)

Solvent: A: 0.05% TFA/H₂O, B: MeCN

Gradient condition: 0.0 to 1.7 minutes Linear gradient of B 10% to B 99%Flow rate: 0.5 mL/min

UV: 220 nm and 254 nm

Column temperature: 40° C.

Powder X-ray diffraction measurements in Examples were carried out inthe following conditions. The obtained diffraction patterns (XRDspectra) are shown in FIG. 1 to FIG. 5.

Crystalline forms may be identified based on distinctive diffractionpeaks of each crystal shown in diffraction diagrams of FIG. 1 to FIG. 5.

Main diffraction peaks and distinctive diffraction peaks which areidentified from diffraction patterns of FIG. 1 to FIG. 5 arerespectively shown below. Diffraction peak values in diffraction angle2θ (°) described in the following Examples include some measurementerrors depending on detection apparatus or measurement conditions etc.Specifically, measurement errors may be within ±0.2, preferably within±0.1.

Measurement method for powder X-ray diffraction:Detection apparatus: Spectris Power X-ray diffraction system EmpyrianX-Ray tube: CuKα (wavelength: 1.54 angstrom)Tube voltage: 45 kVTube current: 40 mAMeasurement range: 4° to 40° (20)Step width: 0.013°Integrated time: 100 sec/step

Reference Example 12-[(4-Chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide

a) Preparation of 5-fluoro-2-methoxy-N,N-di(propan-2-yl)benzamide

5-Fluoro-2-methoxybenzoic acid (100 g) was dissolved in dichloromethane(1.0 L), and diisopropylamine (251 mL) and HATU (235 g) were addedthereto at 0° C. The mixture was stirred at room temperature for a day.The reaction mixture was quenched with 5 mol/L aqueous hydrochloricacid. The resulting solution was extracted twice with ethyl acetate. Theresulting organic layer was washed with brine, dried over magnesiumsulfate, and filtrated, and the solvent was removed under reducedpressure to yield a crude product of the titled compound (200 g).

LC-MS; [M+H]⁺ 254.0/Rt (minutes) 0.96 (Analytical condition A)

b) Preparation of 5-fluoro-2-hydroxy-N,N-di(propan-2-yl)benzamide

5-Fluoro-2-methoxy-N,N-di(propan-2-yl)benzamide (70.0 g) was dissolvedin dichloromethane (400 mL), and boron tribromide (39.2 mL) were addedthereto at 0° C. The mixture was stirred at 0° C. for a day. The mixturewas quenched with 8 mol/L aqueous ammonia. The resulting solution wasextracted twice with chloroform. The resulting organic layer was washedwith brine, dried over magnesium sulfate, and filtered, and the solventwas removed under reduced pressure to yield the titled compound (56.0g).

LC-MS; [M+H]⁺ 240.0/Rt (minutes) 0.85 (Analytical condition A)

c) Preparation of5-fluoro-N,N-di(propan-2-yl)-2-[(pyrimidin-5-yl)oxy]benzamide

5-Fluoro-2-hydroxy-N,N-di(propan-2-yl)benzamide (118.0 g) was suspendedin DMF (250 mL), and 5-bromopyrimidine (35.9 g) and cesium carbonate(73.5 g) were added thereto at room temperature. The mixture was stirredwith heating under reflux for a day. After cooling, the reaction mixturewas concentrated under reduced pressure, and the residue was quenched byaddition of saturated aqueous sodium bicarbonate. The resulting solutionwas extracted twice with ethyl acetate. The resulting organic layer waswashed with brine, dried over magnesium sulfate, and filtered, and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate) to yield thetitled compound (20.0 g).

LC-MS; [M+H]⁺ 317.7/Rt (minutes) 0.86 (Analytical condition A)

d) Preparation of5-fluoro-2-[(1-oxo-1λ⁵-pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide

5-Fluoro-N,N-di(propan-2-yl)-2-[(pyrimidin-5-yl)oxy]benzamide (72.1 g)is dissolved in dichloromethane (900 mL), and meta-chloroperoxybenzoicacid (112 g) was added thereto at 0° C. The mixture was stirred at 0° C.for 2 days. The reaction was quenched with tributylphosphine (56.7 mL)and saturated aqueous sodium bicarbonate. After cooling, dichloromethanewas removed under reduced pressure, and the resulting solution wasextracted twice with ethyl acetate. The resulting organic layer waswashed with brine, dried over magnesium sulfate, and filtered, and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform/methanol) to yield thetitled compound (42.3 g).

LC-MS; [M+H]⁺ 334.0/Rt (minutes) 0.76 (Analytical condition A)

e) Preparation of2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide(Reference Example 1)

5-Fluoro-2-[(1-oxo-1λ⁵-pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide(36.0 g) was dissolved in chloroform (300 mL), andN,N-diisopropylethylamine (37.6 mL) and phosphoryl chloride (40 mL) wereadded thereto at 0° C. The mixture was stirred at 0° C. for 6 hours.After cooling, the reaction mixture was concentrated under reducedpressure, and quenched by addition of saturated aqueous sodiumbicarbonate. The resulting solution was extracted twice with ethylacetate. The resulting organic layer was washed with brine, dried overmagnesium sulfate, and filtered, and the solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to yield the titled compound (27.8g).

¹H-NMR (DMSO-D₆) δ: 8.77 (1H, s), 8.24 (1H, s), 7.53-7.30 (3H, m),3.68-3.61 (1H, m), 3.54-3.48 (1H, m), 1.37 (3H, d, J=6.7 Hz), 1.19 (3H,d, J=7.3 Hz), 1.08 (6H, d, J=6.7 Hz).

LC-MS; [M+H]⁺ 351.9/Rt (minutes) 1.00 (Analytical condition A)

Reference Example 22-{[4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide

a) Preparation of tert-butyl2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

2-[(4-Chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide(27.0 g) was dissolved in 2-propanol (500 mL), andN,N-diisopropylethylamine (40.1 mL) and tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (30.3 g) wereadded thereto at 0° C. The mixture was stirred at room temperature for 6hours. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography(hexane/ethyl acetate) to yield the titled compound (33.0 g).

LC-MS; [M+H]⁺ 542.1/Rt (minutes) 1.23 (Analytical condition A)

b) Preparation of2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide(Reference Example 2)

tert-Butyl2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(44.0 g) was dissolved in dichloromethane (500 mL), and TFA (65 mL) wasadded thereto at 0° C. The mixture was stirred at room temperature for12 hours. The reaction mixture was concentrated under reduced pressure,and the residue was purified by amine-silica gel column chromatography(chloroform/methanol) to yield the titled compound (35.0 g).

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, s), 7.73 (1H, s), 7.24-7.19 (2H, m),7.03-7.00 (1H, m), 3.87-3.78 (4H, m), 3.71-3.67 (1H, m), 3.54-3.51 (1H,m), 2.58-2.55 (4H, m), 1.59-1.56 (4H, m), 1.44 (3H, d, J=6.7 Hz), 1.35(3H, d, J=6.7 Hz), 1.09 (3H, d, J=6.7 Hz), 1.00 (3H, d, J=6.7 Hz).

LC-MS; [M+H]⁺ 442.3/Rt (minutes) 1.33 (Analytical condition B)

Reference Example 32-{[4-(2,6-Diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide

a) Preparation of tert-butyl6-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

The titled compound (1.4 g) was prepared according to a similarprocedure to step a) of Reference example 2 by using2-[(4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide(1.0 g) and 2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butylester hemioxalate (1.0 g).

LC-MS; [M+H]⁺ 514.1/Rt (minutes) 0.96 (Analytical condition A)

b) Preparation of2-{[4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide(Reference Example 3)

The titled compound (1.0 g) was prepared according to a similarprocedure to step b) of Reference example 2 by using tert-butyl6-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.4 g).

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, s), 7.74 (1H, s), 7.23-7.17 (2H, m),6.99-6.96 (1H, m), 4.25-4.23 (2H, m), 4.15-4.12 (2H, m), 3.69-3.66 (1H,m), 3.52-3.50 (5H, m), 1.43 (3H, d, J=6.7 Hz), 1.33 (3H, d, J=6.7 Hz),1.07 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz).

LC-MS; [M+2H]²⁺ 207.5/Rt (minutes) 0.64 (Analytical condition A)

Reference Example 42-{[4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide

a) Preparation of tert-butyl7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

2-[(4-Chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide(150 mg) was dissolved in 2-propanol (10 mL), and triethylamine (0.2 mL)and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (193 mg) wereadded thereto at 0° C. The mixture was stirred at room temperature for 6hours. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography(hexane/ethyl acetate) to yield the titled compound (169 mg).

LC-MS; [M+H]⁺ 542.1/Rt (minutes) 1.22 (Analytical condition A)

b) Preparation of2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide(Reference Example 4)

tert-Butyl7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(169 mg) was dissolved in dichloromethane (10 mL), and TFA (2.0 mL) wasadded thereto at 0° C. The mixture was stirred at room temperature for12 hours. The reaction mixture was concentrated under reduced pressure,and the residue was purified by amine-silica gel column chromatography(chloroform/methanol) to yield the titled compound (122 mg).

LC-MS; [M+H]^(|) 442.3/Rt (minutes) 1.12 (Analytical condition A)

Reference Example 5(1S,3S,4S,5R)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid Reference Example 6(1S,3S,4R,6S)-2-(tert-Butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid

a) Preparation of ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate

To (R)-1-phenylethylamine (63 mL) was added ethyl oxoacetate (100 mL),and the mixture was stirred at room temperature for an hour, andconcentrated under reduced pressure to yield a crude produce of thetitled compound. The resulting compound was used without purification inthe next reaction.

b) Preparation of ethyl(1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate

To a solution of crude ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetateobtained in the above step a) in dichloromethane (475 mL) were addedmolecular sieves 4A (powder, 10 g), and the reaction mixture was cooledto −70° C. Trifluoroacetic acid (32 mL) and boron trifluoride-diethylether complex (53 mL) were added dropwise to the reaction mixture, andthe mixture was stirred for 15 minutes, and 1,3-cyclohexadiene (42 mL)was added dropwise thereto. The reaction mixture was warmed to roomtemperature, and stirred overnight. To the reaction mixture was addedsaturated aqueous sodium bicarbonate, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate. To the organic layer was added sodium sulfate, andthe mixture was dried and filtered. The solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to yield the titled compound (59.4g).

LC-MS; [M+H]⁺ 286.2/Rt (minutes) 0.53 (Analytical condition A)

c) Preparation of a mixture of ethyl(1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylateand ethyl(1S,3S,4R,6S)-6-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate

To a solution of ethyl(1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate(85.5 g) in THF (500 mL) was added dropwise 1.0 mol/L borane-THF complex(300 mL) at 0 to 5° C., and the mixture was stirred at room temperatureovernight. To the reaction mixture were added 3 mol/L aqueous sodiumhydroxide (62 mL) and 30% aqueous hydrogen peroxide (62 mL) underice-cooling, and the mixture was stirred for 30 minutes. Aqueous sodiumthiosulfate was added thereto, and the mixture was stirred for an hour.To the reaction mixture was added ethyl acetate/chloroform, and themixture was separated with a separating funnel. The organic layer waswashed with brine. The organic layer was dried over sodium sulfate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield a crude product of the titled compound (51.7 g) as amixture of regioisomers.

LC-MS; [M+H]^(|) 304.2/Rt (minutes) 0.53 (Analytical condition A)

d) Preparation of ethyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate andethyl (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate

To a solution of the mixed product (51.7 g) obtained in the above stepc) in ethanol (500 mL) was added 10% palladium hydroxide (10.2 g), andthe mixture was stirred at room temperature under a pressurized hydrogengas atmosphere (0.3 to 0.4 MPa) for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol) to yield the titled compounds, ethyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (19.0 g)and ethyl(1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (5.05g).

-   Ethyl    (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate

LC-MS; [M+H]⁺ 200.2/Rt (minutes) 0.27 (Analytical condition A)

-   Ethyl    (1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate-   LC-MS; [M+H]⁺ 200.1/Rt (minutes) 0.36 (Analytical condition A)

e) Preparation of(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 5)

To a solution of ethyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (10.48g) in 1,4-dioxane (153 mL) was added 1 mol/L aqueous sodium hydroxide(238 mL), and the mixture was stirred at room temperature for an hour,cooled to 0° C. Di-tert-butyl dicarbonate (11.48 g) was added thereto.After stirring for an hour, 1 mol/L hydrochloric acid was added theretoto acidify the reaction mixture. Brine was added thereto, and themixture was extracted with a mixed solvent of 10% ethanol/chloroform.The organic layer was dried over sodium sulfate. After filtration, thesolvent was removed under reduced pressure. The residue was washed withdiisopropyl ether, and the mixture was filtered out and dried to yieldthe titled compound (8.40 g).

¹H-NMR (DMSO-D₆) δ: 12.55 (1H, br s), 4.86 (1H, br s), 3.96-3.81 (3H,m), 2.09-1.69 (4H, m), 1.59-1.49 (1H, m), 1.36 (3H, s), 1.31 (6H, s),1.29-1.17 (2H, m).

f) Preparation of(1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 6)

The titled compound (1.60 g) was prepared according to a similarprocedure to step e) by using ethyl(1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (5.05g).

¹H-NMR (DMSO-D₆) δ: 4.09-4.05 (3H, m), 2.28-2.20 (1H, m), 2.18-2.05 (2H,m), 1.91-1.80 (1H, m), 1.63-1.50 (3H, m), 1.45 (3H, s), 1.40 (6H, s).

Reference Example 7(1S,3S,4S,5R)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylicacid

a) Preparation of ethyl(1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

The titled compound (10.8 g) was prepared according to a similar methodto step b) of Reference example 5 by using ethyl(2E)-{[(1R)-1-phenylethyl]imino}acetate (12.0 g) and cyclopentadiene(4.92 mL).

LC-MS; [M+H]⁺ 272.2/Rt (minutes) 0.54 (Analytical condition A)

b) Preparation of ethyl(1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate

The titled compound (7.49 g) was prepared according to a similar methodto step c) of Reference example 5 by using ethyl(1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate(10.8 g).

LC-MS; [M+H]⁺ 290.2/Rt (minutes) 0.46 (Analytical condition A)

c) Preparation of ethyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate

The titled compound (2.89 g) was obtained by a similar method to step d)of Reference example 5 by using ethyl(1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate(7.49 g).

LC-MS; [M+H]⁺ 186.1/Rt (minutes) 0.27 (Analytical condition A)

d) Preparation of(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (Reference Example 7)

The titled compound (980 mg) was prepared according to a similar methodto step e) of Reference example 5 by using ethyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (2.88g).

¹H-NMR (DMSO-D) δ: 4.99 (1H, br s), 4.11-3.95 (1H, m), 3.95-3.82 (1H,m), 3.48-3.40 (1H, m), 2.41-2.31 (1H, m), 1.90-1.75 (1H, m), 1.69-1.49(2H, m), 1.45-1.19 (10H, m).

Reference Example 8 3-Benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

To a solution of(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid (28.0 g) and potassium carbonate (28.5 g) in acetonitrile (300 mL)was added benzyl bromide at room temperature, and the mixture wasstirred overnight. The reaction mixture was concentrated under reducedpressure, and water was added to the residue. The mixture was extractedwith ethyl acetate. The organic layer was dried over sodium sulfate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the titled compound (33.1 g).

LC-MS; [M+H]⁺ 362.3/Rt (minutes) 0.95 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (ReferenceExample 8)

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(33.0 g) in dichloromethane (400 mL) was added Dess-Martin reagent (46.5g) at room temperature, and the mixture was stirred at room temperatureovernight. To the reaction mixture was added aqueous sodium thiosulfateand aqueous sodium bicarbonate, and the mixture was extracted withchloroform. The organic layer was dried over sodium sulfate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield a crude product (33.8 g) of the titled compound.

LC-MS; [M+H]⁺ 360.2/Rt (minutes) 1.02 (Analytical condition A)

¹H-NMR (CDCl₃) δ: 7.38-7.28 (5H, m), 5.33-5.05 (2H, m), 4.66-4.42 (2H,m), 2.80-2.69 (1H, m), 2.59-2.45 (1H, m), 2.36-2.16 (2H, m), 1.82-1.62(3H, m), 1.45 (2.5H, s), 1.31 (6.5H, s).

Reference Example 9(1S,3S,4S)-2-(tert-Butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylicacid

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.0 g) inmethanol (30 mL) was added 5 mol/L aqueous sodium hydroxide (2.7 mL),and the mixture was stirred under heat at 50° C. for 5 hours. After thereaction mixture was cooled to room temperature, it was neutralized with1 mol/L hydrochloric acid and extracted with chloroform. The organiclayer was dried over sodium sulfate and filtered, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform/methanol) to yield the titled compound(0.42 g).

LC-MS; [M+H]⁺ 270.0/Rt (minutes) 0.59 (Analytical condition A)

Reference Example 10(1S,3S,4R)-2-(tert-Butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.0 g) inTHF (30 mL) was added Petasis reagent (5% solution of THF/toluene, 35 g)at room temperature, and the mixture was stirred at 95° C. for 5 hours.The temperature was backed to room temperature, and Petasis reagent (5%solution of THF/toluene, 10 g) was added. The mixture was heated underreflux at 130° C. After cooling, diethyl ether was added thereto, aprecipitated orange solid was filtered off, and the eluent wasconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to yield the titled compound (1.9g).

LC-MS; [M+H]⁺ 358.0/Rt (minutes) 1.21 (Analytical condition A)

b) Preparation of(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 10)

The titled compound (0.99 g) was prepared according to a similar methodto Reference example 9 by using 3-benzyl 2-tert-butyl(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(1.9 g).

LC-MS; [M+H]⁺ 268.0/Rt (minutes) 0.83 (Analytical condition A)

Reference Example 11(1S,3S,4R)-2-(tert-Butoxycarbonyl)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

The titled compound (65.5 g) was prepared according to a similar methodto step a) of Reference example 8 by using(1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylicacid (80.0 g).

LC-MS; [M+H]⁺ 362.1/Rt (minutes) 0.95 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R)-6-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

The titled compound (6.0 g) was prepared according to a similar methodto step b) of Reference example 8 by using 3-benzyl 2-tert-butyl(1S,3S,4R,6S)-6-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(10.0 g).

LC-MS; [M+H]⁺ 360.1/Rt (minutes) 1.02 (Analytical condition A)

c) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

The titled compound (2.12 g) was prepared according to a similar methodto step a) of Reference example 10 by using 3-benzyl 2-tert-butyl(1S,3S,4R)-6-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (4.0 g).

LC-MS; [M+H]⁺ 358.0/Rt (minutes) 1.29 (Analytical condition A)

d) Preparation of(1S,3S,4R)-2-(tert-butoxycarbonyl)-6-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 11)

The titled compound (1.4 g) was prepared according to a similar methodto Reference example 9 by using 3-benzyl 2-tert-butyl(1S,3S,4R)-6-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(2.1 g).

LC-MS; [M+H]⁺ 268.0/Rt (minutes) 0.82 (Analytical condition A)

Reference Example 12 3-Benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

The titled compound (1.73 g) was prepared according to a similar methodto step a) of Reference example 8 by using(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (1.5 g).

LC-MS; [M+H]⁺ 348.2/Rt (minutes) 0.92 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (ReferenceExample 12)

The titled compound (1.40 g) was obtained according to a similar methodto step b) of Reference example 8 by using 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate(1.73 g).

LC-MS; [M+H]⁺ 346.2/Rt (minutes) 1.01 (Analytical condition A)

Reference Example 13(1S,3S,4R)-2-(tert-Butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylicacid

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

The titled compound (1.10 g) was prepared according to a similar methodto step a) of Reference example 10 by using 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.40 g).

LC-MS; [M+H]⁺ 344.2/Rt (minutes) 1.18 (Analytical condition A)

b) Preparation of(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (Reference Example 13)

The titled compound (0.69 g) was prepared according to a similar methodto Reference example 9 by using 3-benzyl 2-tert-butyl(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate(1.10 g).

LC-MS; [M+H]⁺ 254.3/Rt (minutes) 0.82 (Analytical condition A)

Reference Example 14 3-Benzyl 2-tert-butyl(1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.8 g) inN,N-dimethylformamide (180 mL) was added Bredereck reagent (32.8 g), andthe mixture was stirred with heating at 100° C. for 2 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield a crude product of the titled compound (39.0 g)

LC-MS; [M+H]⁺ 415.4/Rt (minutes) 0.95 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(Reference Example 14)

A solution of 3-benzyl 2-tert-butyl(1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(39.0 g) in tetrahydrofuran (300 mL) was cooled to 0° C., andcyclopropylmagnesium bromide (0.5 mol/L aqueous tetrahydrofuran, 245 mL)was added dropwise thereto. The mixture was stirred at room temperaturefor 6 hours. To the reaction mixture was added saturated aqueousammonium chloride, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and filtered, and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate) to yield thetitled compound (32.3 g).

LC-MS; [M+H]⁺ 412.4/Rt (minutes) 1.16 (Analytical condition A)

¹H-NMR (CDCl₃) δ: 7.39-7.27 (5H, in), 5.91 (1H, t, J=11.0 Hz), 5.38-5.04(3H, m), 4.50-4.36 (1H, m), 2.90-2.76 (1H, m), 2.37-2.22 (1H, m),1.82-1.59 (4H, m), 1.44 (3H, s), 1.31 (6H, s), 1.09-0.95 (2H, m),0.73-0.58 (2H, m).

Reference Example 15 3-Benzyl 2-tert-butyl(1S,3S,4S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(32.3 g) in tetrahydrofuran (300 mL) was added copper(I) hydridetriphenylphosphine hexamer (38.5 g), and the mixture was stirred at roomtemperature for 12 hours. The reaction mixture was filtered throughCelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the titled compound (23.2 g) as a mixture ofstereoisomers.

LC-MS; [M+H]⁺ 414.1/Rt (minutes) 1.22 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(Reference Example 15)

A solution of 3-benzyl 2-tert-butyl(1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(23.2 g) in methanol (200 mL) was cooled to 0° C., sodium borohydride(2.12 g) was added thereto, and the mixture was stirred for an hour. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the titled compound as a stereoisomer mixture in lowpolarity (9.3 g) and a stereoisomer mixture in high polarity (10.2 g).

The stereoisomer mixture in low polarity: 3-benzyl 2-tert-butyl(1S,3S,4S,5S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 416.1/Rt (minutes) 1.13 (Analytical condition A)

The stereoisomer mixture in high polarity: 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 416.1/Rt (minutes) 1.01 (Analytical condition A)

Reference Example 16(1S,3S,4S,5R,6R)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid Reference Example 17(1S,3S,4S,5R,6S)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid Reference Example 18(1S,3S,4S,5S,6R)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid Reference Example 19(1S,3S,4S,5S,6S)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylateand 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

A solution of 3-benzyl 2-tert-butyl(1S,3S,4S,5S)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(9.3 g) which is the stereoisomer mixture in high polarity in Referenceexample 15, in dichloromethane (80 mL) was cooled to 0° C., anddiethylaminosulfur trifluoride (5.91 mL) was added thereto. The mixturewas stirred at room temperature overnight. To the reaction mixture wasadded saturated aqueous sodium bicarbonate, and the mixture wasextracted with chloroform. The organic layer was dried over sodiumsulfate and filtered, and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to yield 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(3.6 g) and 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(3.7 g).

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]^(|) 418.4/Rt (minutes) 1.29 (Analytical condition A)

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 418.4/Rt (minutes) 1.35 (Analytical condition A)

b) Preparation of(1S,3S,4S,5R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 16)

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(3.6 g) and ammonium formate (5.4 g) in tetrahydrofuran (50 mL) wasadded palladium hydroxide/carbon (1.2 g), and the mixture was heatedunder reflux for 3 hours. The reaction mixture was cooled to roomtemperature, filtered through Celite, and the filtrate was concentratedunder reduced pressure to yield the titled compound (2.8 g).

LC-MS; [M−H]⁻ 326.4/Rt (minutes) 0.95 (Analytical condition A)

c) Preparation of(1S,3S,4S,5R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 17)

A crude product (108 mg) of the titled compound was prepared accordingto a similar method to step b) of Reference example 16 by using 3-benzyl2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(108 mg).

LC-MS; [M−H]⁻ 326.4/Rt (minutes) 0.95 (Analytical condition A)

d) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylateand 3-benzyl 2-tert-butyl(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

3-Benzyl 2-tert-butyl(1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(86 mg) and 3-benzyl 2-tert-butyl(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(152 mg) were prepared according to a similar method to step a) ofReference example 16 by using 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(363 mg), which is the stereoisomer mixture in high polarity inReference example 15.

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 418.4/Rt (minutes) 1.27 (Analytical condition A)

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 418.4/Rt (minutes) 1.29 (Analytical condition A)

e) Preparation of(1S,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 18)

A crude product (73 mg) of the titled compound was prepared according toa similar method to step b) of Reference example 16 by using 3-benzyl2-tert-butyl(1S,3S,4S,5S,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(82 mg).

LC-MS; [M−H]⁻ 326.4/Rt (minutes) 0.94 (Analytical condition A)

f) Preparation of(1S,3S,4S,5S,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 19)

A crude product (140 mg) of the titled compound was prepared accordingto a similar method to step b) of Reference example 16 by using 3-benzyl2-tert-butyl(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(147 mg).

LC-MS; [M−H]⁻ 326.3/Rt (minutes) 0.95 (Analytical condition A)

Reference Example 20(1S,3S,4R,6S)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid Reference Example 21(1S,3S,4R,6R)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylateand 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

A solution of 3-benzyl 2-tert-butyl(1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(7.3 g) which is the stereoisomer mixture in high polarity in Referenceexample 15, in acetonitrile (50 mL) was cooled to 0° C., and4-(dimethylamino)pyridine (8.6 g) and phenyl chlorothionoformate (4.74mL) were added thereto. The mixture was stirred at 50° C. for 12 hours.The reaction mixture was cooled to room temperature, brine was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate and filtered, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to yield a crude product(1.80 g) of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate,and a crude product (7.90 g) of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate.

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 552.2/Rt (minutes) 1.42 (Analytical condition A)

-   3-Benzyl 2-tert-butyl    (1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

LC-MS; [M+H]⁺ 552.2/Rt (minutes) 1.45 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

A solution of 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(1.80 g) in toluene (50 mL) was cooled to 0° C., andtris(trimethylsilyl)silane (5.03 mL) and2,2′-azobis(2-methylpropionitrile) (0.11 g) were added thereto. Themixture was stirred with heating at 50° C. for 5 hours. The reactionmixture was cooled to room temperature, brine was added thereto, and themixture was extracted with ethyl acetate. The organic layer was driedover magnesium sulfate and filtered, and the solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to yield the titled compound (0.80g).

LC-MS; [M+H]⁺ 400.2/Rt (minutes) 1.38 (Analytical condition A)

c) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

The titled compound (5.50 g) was prepared according to a similar methodto step b) of Reference example 20 by using 3-benzyl 2-tert-butyl(1S,3S,4S,5R,6S)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(7.90 g).

LC-MS; [M+H]⁺ 400.2/Rt (minutes) 1.40 (Analytical condition A)

d) Preparation of(1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 20)

The titled compound (3.90 g) was prepared according to a similar methodto step b) of Reference example 16 by using 3-benzyl 2-tert-butyl(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(5.50 g).

LC-MS; [M+H]⁺ 310.2/Rt (minutes) 1.02 (Analytical condition A)

e) Preparation of(1S,3S,4R,6R)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (Reference Example 21)

The titled compound (980 mg) was prepared according to a similar methodto step b) of Reference example 16 by using 3-benzyl 2-tert-butyl(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate(1.20 g).

LC-MS; [M+H]⁺ 310.2/Rt (minutes) 1.04 (Analytical condition A)

Reference Example 22 tert-Butyl(1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate

To a solution of2-{[4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide(164 mg) obtained in Reference example 2 in chloroform (2 mL) were added(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylicacid (100 mg) obtained in Reference example 9, WSCI.HCl (85 mg), HOBt(68 mg), and N,N-diisopropylethylamine (0.13 mL), and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded water, and the mixture was extracted with chloroform. Theresulting organic layer was dried over sodium sulfate and filtered, andthe solvent was removed under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate) to yield thetitled compound (245 mg).

LC-MS; [M+H]^(|) 693.2/Rt (minutes) 0.97 (Analytical condition A)

Reference Example 23 tert-Butyl(1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-(methoxyimino)-2-azabicyclo[2.2.2]octane-2-carboxylate

To a solution of tert-butyl(1S,3S,4S)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate(100 mg) obtained in Reference example 22 in ethanol (1 mL) and water (2mL) were added O-methylhydroxylamine hydrochloride (24 mg) and sodiumacetate (35 mg), and the mixture was stirred at 75° C. for 3 hours. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The resulting organic layer was dried over sodium sulfateand filtered, and the solvent was removed under reduced pressure toyield the titled compound (89 mg).

LC-MS; [M+H]⁺ 722.6/Rt (minutes) 0.98 (Analytical condition A)

Reference Example 24 tert-Butyl(1R,3S,4R)-3-[7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate

The titled compound (100 mg) was prepared according to a similar methodto Reference example 22 by using2-{[4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl]oxy}-5-fluoro-N,N-di(propan-2-yl)benzamide(122 mg) obtained in Reference example 4 and(1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylicacid (85 mg) which is commercially available.

LC-MS; [M+H]⁺ 679.0/Rt (minutes) 1.89 (Analytical condition B)

Reference Example 25 to 40

The following Reference examples 25 to 40 were prepared according tosimilar methods to Reference example 22 by using each correspondingstarting compound.

LC-MS; [M + H]⁺/ Ref. Rt (min) Example b d E (Analytical condition) 25 22

733.4/2.07 (Analytical condition B) 26 1 1

705.3/1.11 (Analytical condition A) 27 2 2

733.2/1.19 (Analytical condition A) 28 1 1

705.2/1.11 (Analytical condition A) 29 2 2

691.2/1.18 (Analytical condition A) 30 1 1

663.2/1.03 (Analytical condition A) 31 2 2

691.3/1.02 (Analytical condition A) 32 1 1

663.3/1.04 (Analytical condition A) 33 1 1

669.4/1.09 (Analytical condition A) 34 1 1

651.3/1.00 (Analytical condition A) 35 2 2

751.3/1.45 (Analytical condition A) 36 1 1

637.2/1.15 (Analytical condition A) 37 2 2

665.3/1.15 (Analytical condition A) 38 2 2

695.3/0.92 (Analytical condition A) 39 2 2

677.2/1.63 (Analytical condition B) 40 2 2

751.4/2.06 (Analytical condition B)

Reference Example 41 tert-Butyl(1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-(2H2)methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate

a) Preparation of 3-benzyl 2-tert-butyl(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

To a suspension of (²H₃)methyl(triphenyl)phosphonium iodide (2.83 g) inTHF (14 mL) was added dropwise n-butyllithium (1.57 mol/L hexanesolution, 3.54 mL), and the mixture was stirred at 0° C. for 1.5 hours.The reaction was cooled again to −78° C., and 3-benzyl 2-tert-butyl(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.0 g) wasadded portionwise. The mixture was stirred for 5 hours. The reaction wasbacked to room temperature, quenched by addition of saturated aqueousammonium chloride, and the mixture was extracted with ethyl acetate. Theresulting organic layer was washed with water and brine, dried overanhydrous sodium sulfate, and filtered. The solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to yield the titled compound (0.46g).

LC-MS; [M+H]⁺ 360.4/Rt (minutes) 1.22 (Analytical condition A)

b) Preparation of(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid

To a solution of 3-benzyl 2-tert-butyl(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylatein methanol (10 mL) were added aqueous sodium hydroxide (5 mol/L, 1.8mL) and water (2 mL), and the mixture was stirred at 50° C. for 4 hours.The reaction mixture was cooled to room temperature, and the methanolwas removed under reduced pressure. The resulting solution was extractedwith chloroform. The aqueous layer was acidified with 1 mol/Lhydrochloric acid, and extracted with chloroform. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, and filtered.The solvent was removed under reduced pressure to yield the titledcompound (0.31 g). The resulting compound was used in the next reactionwithout purification.

LC-MS; [M+H]^(|) 270.2/Rt (minutes) 0.89 (Analytical condition A) ¹H-NMR(DMSO-D₆) δ: 12.60 (1H, br s), 4.17-3.95. (total 2H, m), 2.74-2.60(total 1H, m), 2.60-2.43 (total 1H, m), 2.34-2.23 (total 1H, m),1.94-1.54 (total 3H, m), 1.54-1.41 (total 1H, m), 1.41-1.19 (total 9H,m).

c) Preparation of tert-butyl(1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate(Reference Example 41)

The title compound (80 mg) was obtained according to a similar method toReference example 22 by using(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carboxylicacid (36 mg).

LC-MS; [M+H]⁺ 693.6/Rt (minutes) 0.99 (Analytical condition A)

Reference Example 42 tert-Butyl7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

a) Preparation of tert-butyl7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a solution of the compound (20.0 g) obtained in Reference example 5in dichloromethane (200 mL) were added tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (18.4 g), WSCI.HCl (18.4 g),HOBt (13.0 g), and N,N-diisopropylethylamine (16.7 mL) at roomtemperature, and the mixture was stirred at room temperature overnight.To a reaction mixture was added chloroform, and the mixture was washedsequentially with saturated aqueous ammonium chloride, water, and brine.The mixture was dried over anhydrous sodium sulfate, and filtrated. Thesolvent was removed from the filtrate under reduced pressure, and theresulting residue was crystallized with diisopropyl ether/hexane (1/1)to yield the titled compound (33.9 g).

LC-MS; [M+H]⁺ 480.1/Rt (mixture) 0.83 (Analytical condition A)

¹H-NMR (DMSO-D₆) δ: 4.48 and 4.39 (total 1H, each m), 4.27-4.302 (total2H, m), 3.73-3.25 (total 9H, m), 2.41 and 2.32 (total 1H, each m), 2.15(1H, br m), 1.98-1.51 (total 10H, m), 1.46-1.42 (total 13H, m),1.39-1.36 (5H, m).

b) Preparation of tert-butyl7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a solution of oxalyl chloride (8.94 mL) in dichloromethane (300 mL)was added dropwise dimethylsulfoxide (11.1 mL) under a nitrogenatmosphere at −78° C., and the mixture was stirred at −78° C. for 30minutes. A solution of tert-butyl7-[(1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(25.0 g) in dichloromethane (100 mL) was added dropwise thereto at −65°C. or below, and the mixture was stirred at −78° C. for another hour.Triethylamine (36.3 mL) was added dropwise thereto at −78° C., and themixture was backed to room temperature and stirred for additional 30minutes. The reaction mixture was diluted with chloroform, and washedsequentially with saturated aqueous ammonium chloride, water, and brine.The resulting organic layer was dried over anhydrous sodium, andfiltrated. The solvent was removed from the filtrate under reducedpressure, and the residue was crystallized with hexane to yield thetitled compound (22.5 g).

LC-MS; [M+H]⁺ 478.1/Rt (minutes) 0.90 (Analytical condition A)

¹H-NMR (CDCl₃) δ: 4.79 and 4.73 (total 1H, each m), 4.70 and 4.55 (total1H, each m), 3.74-3.25 (total 8H, m), 2.67-2.29 (total 4H, m), 2.01-1.50(total 7H, m), 1.50-1.41 (total 12H, m), 1.39 (6H, s).

c) Preparation of tert-butyl7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(Reference Example 42)

To a suspension of methyl(triphenyl)phosphonium bromide (25.2 g) in THF(300 mL) was added potassium tert-butoxide (7.9 g) with ice-cooling, andthe mixture was stirred for an hour. To the reaction mixture was addedtert-butyl7-[(1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(22.5 g), and the mixture was stirred at room temperature for 2 hours.Methyl(triphenyl)phosphonium bromide (8.4 g) and potassium tert-butoxide(2.6 g) were further added thereto, and the mixture was stirred at roomtemperature for another hour. The reaction mixture was diluted withethyl acetate, and washed with water and brine. The resulting organiclayer was dried over anhydrous sodium sulfate, and filtrated. Thesolvent was removed from the filtrate under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to yield the titled compound (24.2 g).

LC-MS; [M+H]⁺ 476.1/Rt (minutes) 1.09 (Analytical condition A)

¹H-NMR (CDCl₃) δ: 4.94 (1H, br s), 4.78 (1H, m), 4.57 and 4.50 (total1H, each m), 4.38 and 4.23 (total 1H, each br s), 3.77-3.26 (total 8H,m), 2.67-2.49 (total 1H, m), 2.47 and 2.41 (total 1H, each m), 2.38-2.27(total 1H, m), 2.26-2.13 (total 1H, m), 1.98-1.47 (total 7H, m),1.47-1.39 (total 12H, m), 1.37 (6H, s).

Example 12-[(4-{7-[(1S,3S,4R,6S)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide

To a solution of tert-butyl(1S,3S,4R,6S)-6-(cyclopropylmethyl)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate(62 mg) obtained in Reference example 25 in dichloromethane (1 mL) wasadded TFA (1 mL) at room temperature, and the mixture was stirred atroom temperature for an hour. The solvent was removed under reducedpressure, and the residue was purified by amine-silica gel columnchromatography (ethyl acetate/methanol) to yield the titled compound (28mg).

LC-MS; [M+H]⁺ 633.4/Rt (minutes) 1.64 (Analytical condition B)

¹H-NMR (CDCl₃) δ: 8.39 (1H, s), 7.80 (1H, d, J=3.1 Hz), 7.02-6.95 (2H,m), 6.74 (1H, m), 4.03 (2H, m), 3.96-3.86 (3H, m), 3.79 (1H, m),3.67-3.46 (3H, m), 3.30 (2H, brs), 2.85 (1H, brs), 2.16 (1H, m), 2.03(1H, m), 1.80-1.59 (6H, m), 1.53 (3H, d, J=6.7 Hz), 1.48 (3H, d, J=6.7Hz), 1.39-1.23 (4H, m), 1.16-1.08 (7H, m), 0.88 (1H, m), 0.68 (1H, m),0.45-0.37 (2H, m), 0.08-0.03 (2H, m).

Example 22-[(4-{7-[(1R,3S,4R)-2-Azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[4.4]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide

The titled compound (89 mg) was prepared according to a similar methodto Example 1 by using tert-butyl(1R,3S,4R)-3-[7-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate(100 mg) obtained in Reference example 24.

LC-MS: [M+H]⁺ 579.0/Rt (minutes) 1.50 (Analytical condition B)

¹H-NMR (CDCl₃) δ: 8.34-8.30 (1H, m), 7.85-7.79 (1H, in), 7.22-7.18 (2H,m), 6.89-6.80 (2H, m), 3.72-3.23 (11H, m), 2.87-2.69 (1H, m), 1.87-1.54(8H, m), 1.44-1.43 (4H, m), 1.35-1.24 (6H, m), 1.08-1.02 (8H, m),0.88-0.85 (1H, m)

Example 3 to 19

The following compounds of Examples 3 to 19 were prepared according to asimilar method to Example 1 by using each corresponding startingcompound.

LC-MS; [M + H]⁺ or [M + 2H]²⁺/Rt (min) (Analytical condition) Example bd E ¹H-NMR: Chemical Shift 3 1 1

605.3/1.60 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.75 (1H, s), 7.23-7.19 (2H, m), 7.03-6.99 (1H, m), 4.36-4.24 (5H, m),4.04-4.01 (2H, m), 3.67-3.50 (3H, m), 3.31 (4H, brs), 2.62 (1H, brs),1.93-1.90 (2H, m), 1.67 (1H, brs), 1.44-1.23 (4H, m), 1.43 (3H, d, J =6.7 Hz), 1.33 (3H, d, J = 6.7 Hz), 1.08 (3H, d, J = 6.7 Hz), 1.03 (3H,d, J = 6.0 Hz), 0.99 (3H, d, J = 6.7 Hz), 0.67-0.61 (1H, m), 0.38-0.36(2H, m), 0.01-0.00 (2H, m). 4 2 2

633.4/1.62 (Analytical condition B) ¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J =1.2 Hz), 7.80 (1H, d, J = 3.7 Hz), 7.01-6.96 (2H, m), 6.74 (1H, m), 4.03(2H, m), 3.93-3.88 (2H, m), 3.82-3.75 (2H, m), 3.67-3.45 (3H, m), 3.30(2H, brs), 2.88 (1H, brs), 1.95-1.83 (2H, m), 1.78- 1.26 (16H, m),1.14-1.08 (6H, m), 0.90-0.85 (2H, m), 0.70 (1H, m), 0.43-0.37 (2H, m),0.08-0.03 (2H, m). 5 1 1

605.4/1.60 (Analytical condition B) ¹H-NMR (CDCl₃) δ: 8.40 (1H, d, J =1.8 Hz), 7.82 (1H, d, J = 3.7 Hz), 7.00-6.96 (2H, m), 6.69 (1H, m),4.47-4.06 (8H, m), 3.77 (1H, m), 3.51-3.45 (2H, m), 2.80 (1H, m), 1.96-1.26 (16H, m), 1.14-1.08 (6H, m), 0.89-0.85 (2H, m), 0.68 (1H, m),0.43-0.37 (2H, m), 0.04 (2H, m). 6 2 2

591.2/0.73 (Analytical condition A) ¹H-NMR (DMSO-D6) δ : 8.25 (1H, s),7.71 (1H, d, J = 4.3 Hz), 7.22-7.17 (2H, m), 7.01 (1H, m), 4.89 (1H, s),4.69 (1H, s), 3.93 (2H, brs) 3.85 (1H, brs), 3.83 (2H, brs), 3.66 (1H,m), 3.57-3.46 (2H, m), 3.37 (1H, m), 3.26 (2H, brs), 2.97 (1H, d, J =3.0 Hz), 2.43 (1H, brm), 2.33 (1H, brm), 2.27 (1H, brs), 2.22 (1H, dd, J= 2.1, 16.8 Hz), 1.70 (2H, brm), 1.63 (3H, brm), 1.57- 1.49 (1H, m),1.41-1.37 (5H, m), 1.31 (3H, d, J = 6.7 Hz), 1.06 (3H, d, J = 6.7 Hz),0.97 (3H, d, J = 6.7 Hz). 7 1 1

282.6/0.87 (Analytical condition A) ¹H-NMR (DMSO-D₆) δ: 8.29 (1H, d, J =2.4 Hz), 7.76 (1H, d, J = 7.3 Hz), 7.24-7.20 (2H, m), 7.05-7.02 (1H, m),4.89 (1H, s), 4.69 (1H, s), 4.37-4.26 (5H, m), 4.10-4.05 (2H, m),3.70-3.66 (1H, m), 3.55-3.51 (2H, m), 3.32 (4H, brs), 2.96 (1H, s),2.42-2.22 (2H, m), 1.68-1.61 (2H, m), 1.44 (3H, d, J = 6.7 Hz),1.40-1.25 (2H, m), 1.34 (3H, d, J = 6.7 Hz), 1.09 (3H, d, J = 6.7 Hz),0.99 (3H, d, J = 6.7 Hz), 0.88-0.84 (1H, m). 8 2 2

591.2/0.73 (Analytical condition A) ¹H-NMR (DMSO-D₆) δ: 8.26 (1H, s),7.72 (1H, s), 7.26-7.17 (2H, m), 7.07-6.99 (1H, m), 4.80 (1H, d, J = 1.8Hz), 4.64 (1H, d, J = 1.8 Hz), 4.04-3.90 (2H, m), 3.90-3.81 (2H, m),3.79 (1H, s), 3.72-3.60 (1H, m), 3.55-3.27 (5H, m), 3.19 (1H, d, J = 1.8Hz), 2.55-2.42 (3H, m), 2.36-2.24 (1H, m), 1.87 (1H, s), 1.81-1.55 (5H,m), 1.53-1.37 (5H, m), 1.32 (3H, d, J = 6.1 Hz), 1.07 (3H, d, J = 6.7Hz), 0.98 (3H, d, J = 6.7 Hz). 9 1 1

563.6/1.51 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.29 (1H, s),7.76 (1H, s), 7.24-7.19 (2H, m), 7.04-7.00 (1H, m), 4.77 (1H, s), 4.62(1H, s), 4.43-4.23 (5H, m), 4.06-4.02 (2H, m), 3.70-3.49 (3H, m), 3.32(4H, brs), 3.13 (1H, s), 2.38-2.28 (2H, m), 1.96 (1H, s), 1.80-1.72 (1H,m), 1.54- 1.34 (3H, m), 1.44 (3H, d, J = 6.7 Hz), 1.34 (3H, d, J = 6.7Hz), 1.09 (3H, d, J = 6.0 Hz), 1.03 (1H, d, J = 8.5 Hz), 1.00 (3H, d, J= 6.7 Hz). 10 1 1

285.2/0.70 (Analytical condition A) ¹H-NMR (DMSO-D₆) δ: 8.27 (1H, s),7.74 (1H, s), 7.23-7.19 (2H, m), 7.04-7.00 (1H, m), 5.00-4.96 (0.5H, m),4.85-4.80 (0.5H, m), 4.34-4.24 (5H, m), 4.09-4.03 (2H, m), 3.75 (1H, s),3.69-3.50 (2H, m), 3.31 (2H, brs), 2.88 (1H, s), 2.06- 1.98 (2H, m),1.77-1.64 (1H, m), 1.52-1.24 (4H, m), 1.43 (3H, d, J = 6.7 Hz), 1.33(3H, d, J = 6.7 Hz), 1.08 (3H, d, J = 6.7 Hz), 1.03 (1H, d, J = 6.1 Hz),0.99 (3H, d, J = 4.9 Hz). 11 1 1

276.7/0.66 (Analytical condition A) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.76 (1H, s), 7.24-7.20 (2H, m), 7.04-7.00 (1H, m), 4.39-4.23 (6H, m),4.08-4.02 (2H, m), 3.70-3.66 (1H, m), 3.54-3.51 (2H, m), 3.41-3.32 (2H,m), 2.74 (1H, s), 1.70- 1.33 (9H, m), 1.43 (3H, d, J = 6.7 Hz), 1.33(3H, d, J = 6.7 Hz), 1.11-1.08 (1H, m), 1.08 (3H, d, J = 6.7 Hz), 0.99(3H, d, J = 6.7 Hz) 12 2 2

297.1/0.46 (Analytical condition A) ¹H-NMR (CDCl₃) δ: 8.33 (1H, s), 7.75(1H, s), 6.95-6.90 (2H, m), 6.72-6.65 (1H, m), 4.40- 4.26 (1H, m),4.11-3.53 (7H, m), 3.50-3.37 (2H, m), 3.29- 3.12 (2H, m), 3.05-2.84 (1H,m), 2.50-2.21 (3H, m), 2.11- 1.97 (1H, m), 1.90-1.54 (7H, m), 1.47 (3H,d, J = 6.1 Hz), 1.42 (3H, d, J = 6.1 Hz), 1.16-0.99 (6H, m). 13 2 2

622.4/0.53 (Analytical condition A) ¹H-NMR (CDCl₃) δ: 8.37 (1H, s), 7.78(1H, s), 7.02-6.92 (2H, m), 6.76-6.68 (1H, m), 4.21 (1H, s), 4.13-3.65(9H, m), 3.56-3.41 (3H, m), 3.39-3.22 (2H, m), 2.93-2.82 (1H, m),2.58-2.41 (2H, m), 2.02-1.89 (1H, m), 1.89-1.59 (7H, m), 1.59-1.40 (7H,m), 1.20-1.04 (6H, m). 14 2 2

651.5/0.57 (Analytical condition A) ¹H-NMR (DMSO-D₆) δ: 8.31 (1H, s),7.77 (1H, s), 7.31-7.23 (2H, m), 7.12-7.05 (1H, m), 5.09-4.89 (1H, m),4.11-3.85 (5H, m), 3.77-3.65 (1H, m), 3.61-3.44 (3H, m), 3.41-3.23 (3H,m), 2.92 (1H, s), 2.10- 1.95 (2H, m), 1.86-1.26 (15H, m), 1.12 (3H, d, J= 6.7 Hz), 1.03 (3H, d, J = 6.7 Hz), 0.82-0.71 (1H, m), 0.51-0.36 (2H,m), 0.18-0.01 (2H, m). 15 1 1

537.4/1.48 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.75 (1H, s), 7.23-7.19 (2H, m), 7.03-7.00 (1H, m), 4.39-4.22 (5H, m),4.01-3.98 (2H, m), 3.69-3.51 (2H, m), 3.35-3.31 (4H, m), 3.06 (1H, s),2.42 (1H, s), 1.47-0.99 (8H, m), 1.43 (3H, d, J = 6.7 Hz), 1.33 (3H, d,J = 6.7 Hz), 1.08 (3H, d, J = 6.7 Hz), 1.03 (3H, d, J = 6.7 Hz) 16 2 2

565.7/1.58 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.75 (1H, s), 7.26-7.21 (2H, m), 7.05-7.02 (1H, m), 3.98-3.38 (12H, m),2.53 (1H, s), 1.78-1.58 (8H, m), 1.43 (3H, d, J = 6.7 Hz), 1.35-1.33(2H, s), 1.34 (3H, d, J = 6.7 Hz), 1.08 (3H, d, J = 6.7 Hz), 0.98 (3H,d, J = 6.7 Hz) 17 2 2

595.2/1.47 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.74 (1H, s), 7.25-7.22 (2H, m), 7.06-7.04 (1H, m), 4.67 (s, 1H),4.01-3.86 (5H, m), 3.74 (1H, s), 3.73-3.62 (1H, m), 3.32-3.30 (4H, m),2.78 (1H, s), 2.10-2.04 (1H, m), 1.80-1.48 (6H, m), 1.44- 1.40 (1H, m),1.43 (3H, d, J = 6.7 Hz), 1.34 (3H, d, J = 6.7 Hz), 1.26-1.18 (2H, s),1.08 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz) 18 2 2

577.0/1.56 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.28 (1H, s),7.74 (1H, s), 7.25-7.21 (2H, m), 7.05-7.04 (1H, m), 5.01 (s, 1H), 4.67(s, 1H), 3.87-3.85 (2H, m), 3.71-3.64 (1H, m), 3.55-3.48 (3H, m),3.39-3.31 (5H, m), 2.86 (1H, s), 2.14-1.98 (2H, m), 1.77- 1.65 (4H, m),1.43 (3H, d, J = 6.7 Hz), 1.35-1.32 (3H, m), 1.34 (3H, d, J = 6.7 Hz),1.08 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 0.86-0.85 (1H, m).19 2 2

651.4/1.67 (Analytical condition B) ¹H-NMR (DMSO-D₆) δ: 8.27 (1H, s),7.73 (1H, s), 7.25-7.21 (2H, m), 7.07-7.03 (1H, m), 4.55 (s, 1H), 4.42(s, 1H), 4.03-3.85 (5H, m), 3.70-3.65 (1H, m), 3.53-3.49 (1H, m),3.26-3.24 (2H, m), 2.81 (1H, s), 2.04-1.94 (2H, m), 1.71- 1.65 (2H, m),1.43 (3H, d, J = 6.7 Hz), 1.42-1.32 (2H, m), 1.34 (3H, d, J = 6.7 Hz),1.19-1.17 (1H, m), 1.08 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz),0.86-0.85 (1H, m), 0.44-0.42 (2H, m), 0.08-0.04 (2H, m).

Example 205-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide

The titled compound (23 mg) was prepared according to a similar methodto Example 1 by using tert-butyl (1S,3S,4R)-3-[2-(5-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-(²H₂)methylidene-2-azabicyclo[2.2.2]octane-2-carboxylate(80 mg) obtained in Reference example 41.

LC-MS; [M+H]⁺ 593.6/Rt (minutes) 0.70 (Analytical condition A)

1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 7.73 (1H, d, J=4.1 Hz), 7.26-7.16 (2H,m), 7.03 (1H, m), 4.05-3.90 (total 3H, brs), 3.87 (2H, m), 3.67 (1H, m),3.57-3.45 (2H, m), 3.45-3.19 (total 3H, m), 3.07 (1H, s), 2.52 (1H,brs), 2.33 (1H, brs), 2.27 (1H, dd, J=2.5, 17.1 Hz), 1.79-1.60 (total5H, brm), 1.55 (1H, m), 1.48-1.37 (5H, m), 1.33 (3H, d, J=6.9 Hz), 1.07(3H, d, J=6.4 Hz), 0.98 (3H, d, J=6.4 Hz).

Example 212-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidemono-L(+)-tartrate

To a solution of the compound (0.50 g) of Example 4 in ethylacetate/ethanol (10/1, 11 mL) was added L(+)-tartaric acid (0.11 g), andthe mixture was stirred at room temperature for 3 days. The precipitatedsolid was filtered, washed with ethyl acetate, and dried under reducedpressure to yield the titled compound (0.54 g) as a crystal (crystalform I).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.27 (1H, s), 7.74 (1H, s), 7.26-7.18 (2H,m), 7.04 (1H, m), 4.27 (1H, br s), 3.96 (2H, br s), 3.91-3.80 (total 4H,m), 3.67 (1H, m), 3.57-3.43 (3H, m), 3.38 (2H, br s), 3.29 (1H, br s),1.94 (1H, br s), 1.91-1.78 (3H, m), 1.70 (4H, br m), 1.62-1.20 (total12H, m), 1.07 (3H, d, J=6.1 Hz), 0.97 (3H, d, J=6.1 Hz), 0.68 (1H, m),0.40 (2H, m), 0.07 (2H, m).

(Crystal form I) A powder X-ray diffraction pattern was shown in FIG. 1.Main diffraction peak: 2θ (°)=5.3, 8.0, 11.2, 13.0, 13.5, 15.9, 16.4,17.5, 17.9, 18.2, 20.0Distinctive diffraction peak: 2θ (°)=5.3, 11.2, 13.0, 15.9, 17.9, 18.2

Example 222-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidemonohydrochloride

To a solution of the compound (50 mg) of Example 4 in ethyl acetate (1mL) was added 4 mol/L hydrochloric acid/ethyl acetate (19 μL), and themixture was stirred at room temperature for 4 hours. The precipitatedsolid was filtered, washed with ethyl acetate, and dried under reducedpressure to yield the titled compound (30 mg) as a crystal (crystal formII).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.27 (1H, s), 7.75 (1H, d, J=1.8 Hz),7.26-7.19 (2H, m), 7.04 (1H, m), 4.36 (1H, br s), 4.07-3.92 (2H, br s),3.92-3.81 (2H, m), 3.67 (1H, m), 3.61-3.46 (3H, m), 3.45-3.36 (3H, m),2.00 (1H, br s), 1.96-1.80 (3H, m), 1.79-1.21 (total 16H, m), 1.08 (3H,d, J=6.9 Hz), 0.97 (3H, d, J=6.4 Hz), 0.68 (1H, m), 0.41 (2H, m), 0.09(2H, m).

(Crystal form II) A powder X-ray diffraction pattern is shown in FIG. 2.Main diffraction peak: 2θ (°)=5.3, 9.9, 10.6, 11.9, 13.1, 13.6, 15.9,16.3, 17.9, 18.9, 21.2Distinctive diffraction peak: 2θ (°)=5.3, 9.9, 10.6, 15.9, 16.3, 17.9

Example 232-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidedihydrochloride

To a solution of the compound (0.50 g) of Example 4 in ethylacetate/ethanol (10/1, 11 mL) was added 4 mol/L hydrochloric acid/ethylacetate (0.38 mL), and the mixture was stirred at room temperature for 3days. The precipitated solid was filtered, washed with ethyl acetate,and dried under reduced pressure to yield dihydrochloride of thecompound of Example 4 (0.49 g) as a crystal (crystal form III).

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.22 (1H, br s), 8.53 (1H, s), 8.03 (1H, brd, J=12.8 Hz), 7.85 (1H, br s), 7.36-7.25 (3H, m), 4.40 (1H, br s),4.34-3.97 (total 4H, br m), 3.67 (1H, m), 3.59-3.47 (3H, m), 3.46-3.37(3H, m), 2.01 (1H, br s), 1.96-1.82 (3H, m), 1.75 (4H, br s), 1.66-1.27(total 12H, m), 1.09 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz), 0.67(1H, m), 0.40 (2H, m), 0.10 (2H, m).

(Crystal form III) A powder X-ray diffraction pattern is shown in FIG.3.Main diffraction peak: 2θ (°)=4.3, 7.0, 9.9, 10.6, 11.8, 15.2, 15.5,15.9, 16.5, 16.8, 17.9Distinctive diffraction peak: 2θ (°)=4.3, 7.0, 10.6, 15.9, 16.5, 16.8

Example 65-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide

Example 6 can also be prepared by the following procedure. To a solutionof tert-butyl7-[(1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(7.0 g) obtained in Reference example 42 in chloroform (11 mL) was addeddropwise TFA (11 mL) at room temperature, and the mixture was stirred atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, diluted with acetonitrile (70 mL), and 5 mol/L aqueoussodium hydroxide (28 mL) was added dropwise thereto with ice cooling.2-[(4-Chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide(4.9 g) obtained in Reference example 1 was added thereto, and themixture was stirred at room temperature for 5 hours. To the reaction wasadded water (200 mL), and the precipitated solid was filtered, andwashed with water. The solid was dried under reduced pressure to yieldthe titled compound (7.3 g).

Example 245-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamidemono-L (+)-tartrate

To a solution of the compound (2.0 g) of Example 6 in THF (5 mL) wasadded L(+)-tartaric acid (0.48 g), and the mixture was stirred at 60° C.for an hour. After cooling, the precipitated solid was filtered, washedwith ethyl acetate, and dried under reduced pressure to yield the titledcompound (2.0 g) as a crystal (crystal form IV).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.28 (1H, s), 7.73 (1H, d, J=5.5 Hz),7.26-7.17 (2H, m), 7.02 (1H, m), 5.08 (1H, s), 4.85 (1H, s), 4.32 (1H,s), 4.06-3.83 (total 6H, m), 3.68 (1H, m), 3.63-3.39 (total 4H, m), 3.32(2H, br s), 2.66 (1H, m), 2.54 (1H, br s), 2.39 (1H, m), 1.91-1.64(total 5H, m), 1.60-1.47 (3H, m), 1.42 (3H, d, J=6.9 Hz), 1.33 (3H, d,J=6.4 Hz), 1.08 (3H, d, J=6.9 Hz), 0.98 (3H, d, J=6.4 Hz).

(Crystal form IV) A powder X-ray diffraction pattern is shown in FIG. 4.Main diffraction peak: 2θ (°)=5.1, 6.3, 9.0, 10.5, 12.3, 12.6, 13.3,15.3, 17.1, 17.2, 18.0Distinctive diffraction peak: 2θ (°)=5.1, 6.3, 9.0, 15.3, 17.2, 18.0

Example 255-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamidedisuccinate

To a solution of the compound of Example 6 (2.0 g) in ethyl acetate (8mL) was added succinic acid (0.78 g), and the mixture was stirred at 60°C. for an hour. After cooling, the precipitated solid was filtered,washed with ethyl acetate, and dried under reduced pressure to yield thetitled compound (1.9 g) as a crystal (crystal form V).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.27 (1H, s), 7.75 (1H, d, J=4.6 Hz),7.25-7.18 (2H, m), 7.06 (1H, m), 5.03 (1H, s), 4.81 (1H, s), 4.81 (1H,s), 3.96 (2H, br s), 3.87 (2H, br d, J=9.1 Hz), 3.68 (1H, m), 3.60-3.37(total 3H, m), 3.31 (3H, br s), 2.59 (1H, br d, J=17.4 Hz), 2.47 (1H, brs), 2.40-2.27 (total 9H, m), 1.85-1.62 (total 5H, m), 1.57-1.45 (total3H, m), 1.42 (3H, d, J=6.9 Hz), 1.33 (3H, d, J=6.4 Hz), 1.08 (3H, d,J=6.4 Hz), 0.98 (3H, d, J=6.9 Hz).

(Crystal form V) A powder X-ray diffraction pattern is shown in FIG. 5.Main diffraction peak: 2θ (°)=4.9, 8.1, 8.6, 9.8, 13.9, 14.5, 17.2,17.8, 18.4, 19.0, 20.5Distinctive diffraction peak: 2θ (°)=8.1, 8.6, 9.8, 14.5, 17.2, 17.8,18.4

Tests Test 1: Test for Evaluating the Inhibition of the Menin-MLLBinding

Menin₁₋₆₁₅ wherein 6×His tag and HA tag are inserted in the N-terminus,and myc tag is inserted in the C-terminus (hereinafter, referred to asHis-Menin₁₋₆₁₅), is diluted with an assay buffer (25 mmol/L HEPES, 150mmol/L NaCl, 1 mmol/L dithiothreitol, 0.5% (w/v) Tween 80, 0.3% (w/v)BSA, 0.3% (w/v) skim milk) to adjust the final concentration to 30nmol/L. The test compounds are also diluted with the assay buffer toadjust each concentration of the test compounds to 0.005 to 5 μmol/L.The prepared His-Menin₁₋₆₁₅ and test compounds were added to alight-shielding 384-well low-volume plate (Corning, #4514) in 2 μL/welland 6 μL/well, respectively, and the plate was covered with a lid forlight-shielding (Corning, #3935), and incubated at room temperature for3 hours. After the incubation, MLL₁₋₁₇₂ wherein FLAG tag is inserted inthe C-terminus (MLL₁₋₁₇₂-FLAG), was separately diluted with the assaybuffer to adjust the final concentration to 50 nmol/L. The preparedMLL₁₋₁₇₂-FLAG was added to the above plate in 2 μL/well, and the platewas covered with a lid for light-shielding and incubated at roomtemperature for an hour.

Then, anti-6HIS-d2 antibody (cisbio, 61HISDLA) and anti-FLAGM2-Kantibody (cisbio, 61FG2KLA) were diluted with an antibody dilutionbuffer (50 mmol/L Tris, 150 mmol/L NaCl, 800 mmol/L KF, pH 7.4) toadjust the final concentration to 1.4 μg/mL to prepare an antibodymixture. The prepared antibody mixture was added to the above plate in10 μL/well, and the plate was covered with a lid and incubated at 4° C.for 17 to 24 hours. After the incubation, the signal was detected withRUBYstar (BMG LABTECH). The binding inhibition rate (%) at eachconcentration of the test compounds was calculated from the followingformula, and the IC₅₀ value was obtained, that corresponds to theconcentration of the test compound at which the binding inhibition rateis 50%.

Binding inhibition rate (%)={1−(A−C)/(B−C)}×100

A: Signal in the presence of test compoundB: Signal of negative control (in the absence of test compound)C: Signal of positive control (in the presence of known compound at theconcentration which shows 100% inhibition ratio)

The results of the evaluation in Test 1 are shown in the followingtable.

HTRF Example IC₅₀ (nM)  1 5.3  2 —  3 <3.0   4 7.1  5 4.1  6 <3.0   7<3.0   8 7.9  9 6.2 10 <3.0  11 7.0 12 — 13 — 14 — 15 — 16 — 17 — 18 —19 — 20 —

The compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, and 11 showedpotent Menin-MLL binding inhibition activity as shown in the abovetable. Among them, the compounds of Examples 3, 6, 7, and 10 showedparticularly potent Menin-MLL binding inhibition activity.

Test 2: Test for Evaluating the Inhibition of Cell Proliferation

RS4; 11 cells were obtained from American Type Culture Collection(ATCC). The cells were cultured at 37° C. in the presence of 5% CO₂ inRPMI 1640 medium containing 10% fetal bovine serum and 1%penicillin/streptomycin. MOLM-13 cells were separately obtained fromDSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH). Thecells were cultured at 37° C. in the presence of 5% CO₂ in RPMI 1640medium containing 20% fetal bovine serum and 1% penicillin/streptomycin.

The cells were plated to a 96-well plate in 2000 cells/well, each testcompound was added thereto to adjust the final concentration of DMSO to0.1% of DMSO, and the cells were cultured for 7 days. After thecultivation, the cell viability was calculated with PrestoBlue™ CellViability Reagent (Invitrogen, A13261). The IC₅₀ value was calculatedfrom a survival curve that corresponds to the concentration of the testcompound at which the cell proliferation inhibition rate is 50%.

The results of the evaluation in Test 2 are shown in the followingtable.

IC₅₀ (μM) Example RS4; 11 MOLM-13  1 <0.01  0.02  2 0.87 0.81  3 0.030.01  4 0.04 0.07  5 0.02 0.03  6 0.02 0.03  7 0.01 0.03  8 0.09 0.11  90.08 0.08 10 0.02 0.03 11 0.02 0.03 12 0.25 0.25 13 2.40 >3.00  14 0.020.04 15 0.02 0.02 16 0.03 0.04 17 >3.00  1.60 18 0.02 0.04 19 <0.01 <0.01  20 — <0.03 

The compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16,18, 19, and 20 showed the potent cell proliferation inhibition activityas shown in the above table.

Test 3: Test for the Inhibition of mRNA Transcription with TestCompounds

MV4; 11 cells were obtained from American Type Culture Collection(ATCC). The cells were cultured at 37° C. in the presence of 5% CO₂ inRPMI 1640 medium containing 10% fetal bovine serum and 1%penicillin/streptomycin. To the MV4; 11 cells was added each testcompound to adjust the final concentration to 1 μmol/L, and the cellswere cultured at 37° C. in the presence of 5% CO₂ for 20 to 24 hours.After the incubation, the total RNA was extracted from the cells withRNeasy™ Mini Kit (QIAGEN, 74106), and cDNA was synthesized withSuperscript™ VILO™ cDNA Synthesis Kit (Invitrogen, #11754250). By usingTaqMan™ Gene Expression Master Mix (Applied Biosystems, 4369016) andTaqMan™ probe (Applied Biosystems), the expression level of mRNA wasquantified from the obtained cDNA with 7900HT (Applied Biosystems). Theexpression level of each obtained gene (MEIS1 and HOXA9) was fitted withthe expression level of mRNA of GAPDH.

The results of the evaluation in Test 3 are shown in the followingtable.

mRNA at 1 μM (% control) Example MEIS1 HOXA9  1 11.8 40.2  2 — —  3 11.939.6  4 18.0 43.7  5 15.5 42.6  6 15.1 39.3  7 12.7 37.9  8 17.1 40.1  917.0 41.2 10 13.3 37.4 11 13.1 36.5 12 — — 13 — — 14 — — 15 — — 16 — —17 — — 18 — — 19 — — 20 — —

The compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, and 11 showed themRNA transcription inhibition activity which is caused by the bindinginhibition of Menin and a MLL fusion protein. Especially, the compoundof Example 5 showed an excellent cell proliferation inhibitory activity.

Test 4: Test for the hERG Inhibition

To a cultured CHO cell strain which stably expresses hERG (humanEther-a-go-go Related Gene) was added each test compound to adjust thefinal concentration to 0.0135 to 0.5% of DMSO. The hERG current wasmeasured with QPatch HT (Sophion Inc.), and the concentration at which50% of the hERG current was inhibited by each test compound (IC₅₀ value;μM) was calculated.

The compounds of Examples were tested according to Test example 4. And,the hERG/RS4; 11 was calculated by dividing the compound concentrationobtained in Test example 4, at which 50% of the hERG current isinhibited, by the compound concentration obtained in Test example 2, atwhich 50% of the proliferation of RS4; 11 cells is inhibited. Theresults are shown in the following table.

hERG inhibition hERG/ Example IC₅₀ (μM) RS4; 11  1 4.0 >400  2 11.8 13.6 3 6.2 620  4 5.8 145  5 7.9 395  6 51.9 2595  7 >100 >10000  8 12.3 137 9 >10 >125 10 >10 >500 11 >10 >500 12 >100 >400 13 — — 14 11.7 55715 >100 >6250 16 >100 >3571 17 >100 — 18 46.1 >2095 19 6.9 >690 20 74.8—

As shown in the above table, there is a more than 100-fold gap betweenthe concentration at which 50% of the proliferation of RS4; 11 cells wasinhibited and the concentration at which 50% of the hERG current wasinhibited in the compounds of Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 14, 15, 16, 18, and 19. Especially, it is proved that there is amore than 1000-fold excellent gap between the concentration at which 50%of the proliferation of RS4; 11 cells was inhibited and theconcentration at which 50% of the hERG current was inhibited in thecompounds of Examples 6, 7, 15, 16, and 18.

INDUSTRIAL APPLICABILITY

The compounds of the present invention can inhibit the binding of a MLLfusion protein and menin to provide the antitumor effect.

1.2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidemono-L(+)-tartrate in crystal form of form I which is characterized by apowder x-ray diffraction pattern having diffraction angle (2θ°) peaks of5.3°±0.2°, and 13.0°±0.2°.
 2. The compound of claim 1, wherein thecrystal form is characterized by a powder x-ray diffraction patternhaving diffraction angle (2θ°) peaks of 5.3°±0.2°, 11.2°±0.2°,13.0°±0.2°, 15.9°±0.2°, 17.9°±0.2°, and 18.2°±0.2°.
 3. The compound ofclaim 1, wherein the crystal form is characterized by a powder x-raydiffraction pattern having diffraction angle (20°) peaks of 5.3°±0.2°,8.0°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 13.5°±0.2°, 15.9°±0.2°, 16.4°±0.2°,17.5°±0.2°, 17.9°±0.2°, 18.2°±0.2°, and 20.0°±0.2°. 4.2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidemonohydrochloride in crystal form of form II which is characterized by apowder x-ray diffraction pattern having diffraction angle (2θ°) peaks of10.6°±0.2°, 15.9°±0.2°.
 5. The compound of claim 4, wherein the crystalform is characterized by a powder x-ray diffraction pattern havingdiffraction angle (2θ°) peaks of 5.3°±0.2°, 9.9°±0.2°, 10.6°±0.2°,15.9°±0.2°, 16.3°±0.2°, and 17.9°±0.2°.
 6. The compound of claim 4,wherein the crystal form is characterized by a powder x-ray diffractionpattern having diffraction angle (2θ°) peaks of 5.3°±0.2°, 9.9°±0.2°,10.6°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 15.9°±0.2°, 16.3°±0.2°,17.9°±0.2°, 18.9°±0.2°, and 21.2°±0.2°. 7.2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamidedihydrochloride in crystal form of form III which is characterized by apowder x-ray diffraction pattern having diffraction angle (2θ°) peaks of4.3°±0.2°, and 7.0°±0.2°.
 8. The compound of claim 7, wherein thecrystal form is characterized by a powder x-ray diffraction patternhaving diffraction angle (2θ°) peaks of 4.3°±0.2°, 7.0±0.2°, 10.6°±0.2°,15.9°±0.2°, 16.5°±0.2°, 16.8°±0.2°.
 9. The compound of claim 7, whereinthe crystal form is characterized by a powder x-ray diffraction patternhaving diffraction angle (2θ°) peaks of 4.3°±0.2°, 7.0±0.2°, 9.9°±0.2°,10.6°±0.2°, 11.8°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 16.5°±0.2°,16.8°±0.2°, and 17.9°±0.2°. 10.5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamidemono-L(+)-tartrate in crystal form of form IV which is characterized bya powder x-ray diffraction pattern having diffraction angle (2θ°) peaksof 5.1°±0.2°, and 9.0±0.2°.
 11. The compound of claim 10, wherein thecrystal form is characterized by a powder x-ray diffraction patternhaving diffraction angle (2θ°) peaks of 5.1°±0.2°, 6.3°±0.2°, 9.0±0.2°,15.3°+0.2°, 17.2°±0.2°, and 18.0°±0.2°.
 12. The compound of claim 10,wherein the crystal form is characterized by a powder x-ray diffractionpattern having diffraction angle (2θ°) peaks of 5.1°±0.2°, 6.3°±0.2°,9.0°±0.2°, 10.5°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 15.3°±0.2°,17.1°±0.2°, 17.2°±0.2°, and 18.0°±0.2°. 13.5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamidedisuccinate in crystal form of form V which is characterized by a powderx-ray diffraction pattern having diffraction angle (2θ°) peaks of17.2°±0.2°, and 18.4°±0.2°.
 14. The compound of claim 13, wherein thecrystal form is characterized by a powder x-ray diffraction patternhaving diffraction angle (2θ°) peaks 8.1°±0.2°, 8.6°±0.2°, 9.8°±0.2°,14.5°±0.2°, 17.2°±0.2°, 17.8°±0.2° and 18.4°±0.2°.
 15. The compound ofclaim 13, wherein the crystal form is characterized by a powder x-raydiffraction pattern having diffraction angle (2θ°) peaks of 4.9°±0.2°,8.1°±0.2°, 8.6°±0.2°, 9.8°±0.2°, 13.9°±0.2°, 14.5°±0.2°, 17.2°±0.2°,17.8°±0.2°, 18.4°±0.2°, 19.0°±0.2°, and 20.5°±0.2°.